U.S. patent number 7,183,318 [Application Number 10/462,331] was granted by the patent office on 2007-02-27 for substituted cyclic compounds, preparation method and pharmaceutical compositions containing them.
This patent grant is currently assigned to Les Laboratoires Servier. Invention is credited to Caroline Bennejean, Philippe Delagrange, Gerald Guillaumet, Frederique Klupsch, Michel Langlois, Daniel Lesieur, Pierre Renard, Marie-Claude Viaud.
United States Patent |
7,183,318 |
Lesieur , et al. |
February 27, 2007 |
**Please see images for:
( Certificate of Correction ) ** |
Substituted cyclic compounds, preparation method and pharmaceutical
compositions containing them
Abstract
The invention concerns compounds of formula (1): R-A-R' wherein:
A is as defined in the description; R represent a group (V), (VI),
(VII), or (VIII), where E, Q, R.sup.1, R.sup.2, R.sup.3, v and
R.sup.4 are as defined in the description; R' represents a
--(CH.sub.2).sub.t--R.sup.5 group wherein t and R.sup.5 are as
defined in the description, and medicaments containing the same
##STR00001##
Inventors: |
Lesieur; Daniel (Gondecourt,
FR), Klupsch; Frederique (Hulluch, FR),
Guillaumet; Gerald (Saint Jean le Blanc, FR), Viaud;
Marie-Claude (Tours, FR), Langlois; Michel
(Sceaux, FR), Bennejean; Caroline (Charenton le Pont,
FR), Renard; Pierre (Le Chesnay, FR),
Delagrange; Philippe (Issy les Moulineaux, FR) |
Assignee: |
Les Laboratoires Servier
(Courbevoie Cedex, FR)
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Family
ID: |
9526252 |
Appl.
No.: |
10/462,331 |
Filed: |
June 16, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040002491 A1 |
Jan 1, 2004 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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09700056 |
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6605632 |
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PCT/FR99/01101 |
May 10, 1999 |
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Foreign Application Priority Data
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May 12, 1998 [FR] |
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98.05957 |
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Current U.S.
Class: |
514/527; 549/483;
564/161; 514/461 |
Current CPC
Class: |
C07D
407/12 (20130101); C07D 335/06 (20130101); C07D
213/70 (20130101); C07C 237/48 (20130101); C07D
319/20 (20130101); A61P 1/00 (20180101); A61P
25/04 (20180101); C07D 233/84 (20130101); C07D
311/60 (20130101); C07D 333/20 (20130101); A61P
15/08 (20180101); A61P 25/28 (20180101); C07D
261/20 (20130101); C07D 311/58 (20130101); A61P
5/02 (20180101); A61P 25/00 (20180101); C07C
233/62 (20130101); C07D 335/08 (20130101); C07D
249/08 (20130101); C07D 405/06 (20130101); A61P
25/08 (20180101); A61P 35/00 (20180101); C07D
231/12 (20130101); A61P 9/00 (20180101); C07D
209/20 (20130101); C07D 495/04 (20130101); C07D
307/81 (20130101); C07D 333/74 (20130101); C07D
405/12 (20130101); A61P 25/06 (20180101); C07D
235/06 (20130101); C07D 333/38 (20130101); C07D
401/12 (20130101); A61P 25/22 (20180101); A61P
43/00 (20180101); A61P 25/24 (20180101); C07C
323/62 (20130101); A61P 3/10 (20180101); C07D
233/42 (20130101); C07D 207/27 (20130101); A61P
25/16 (20180101); A61P 25/18 (20180101); C07D
209/60 (20130101); A61P 3/06 (20180101); C07D
319/18 (20130101); C07C 275/24 (20130101); C07D
209/14 (20130101); C07C 271/20 (20130101); C07D
221/10 (20130101); C07D 491/04 (20130101); C07C
233/43 (20130101); C07D 233/56 (20130101); C07C
233/65 (20130101); C07D 307/92 (20130101); C07D
495/14 (20130101); C07D 333/58 (20130101); A61P
25/20 (20180101); C04B 35/632 (20130101); C07D
471/04 (20130101); C07C 2602/08 (20170501); C07C
2601/02 (20170501); C07C 2601/14 (20170501); C07C
2602/10 (20170501) |
Current International
Class: |
C07C
233/57 (20060101); A61K 31/165 (20060101); A61K
31/34 (20060101); A61P 25/22 (20060101); A61P
25/24 (20060101); C07C 233/64 (20060101); C07D
307/02 (20060101) |
Field of
Search: |
;564/161
;514/627,527,461 ;549/483 |
Foreign Patent Documents
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|
Primary Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Hueschen and Sage
Claims
We claim:
1. A compound selected from those of formula (I): R-A-R' (I)
wherein: .diamond-solid. A represents: a ring system of formula
(II): ##STR00051## wherein R substitutes the ring B' and R'
substitutes either ring of the ring system of formula (III), it
being understood that the ring system of formula (III) may be
unsubstituted or substituted (in addition to the substituents R and
R') by from 1 to 6 radicals, which may be the same or different,
selected from R.sub.a, OR.sub.a, COR.sub.a, COOR.sub.a, OCOR.sub.a,
OSO.sub.2CF.sub.3 and halogen, wherein R.sub.a represents hydrogen,
unsubstituted or substituted linear or branched (C.sub.1
C.sub.6)alkyl, unsubstituted or substituted linear or branched
(C.sub.2 C.sub.6)alkenyl, unsubstituted or substituted linear or
branched (C.sub.2 C.sub.6)alkynyl, linear or branched (C.sub.1
C.sub.6)polyhaloalkyl, unsubstituted or substituted (C.sub.3
C.sub.8)cycloalkyl, unsubstituted or substituted (C.sub.3
C.sub.8)cycloalkyl-(C.sub.1 C.sub.6)alkyl in which the alkyl group
is linear or branched, unsubstituted or substituted (C.sub.3
C.sub.8)cycloalkenyl, unsubstituted or substituted (C.sub.3
C.sub.8)cycloalkenyl-(C.sub.1 C.sub.6)alkyl in which the alkyl
group is linear or branched, aryl, aryl-(C.sub.1 C.sub.6)alkyl in
which the alkyl moiety is linear or branched, aryl-(C.sub.1
C.sub.6)alkenyl in which the alkenyl moiety is linear or branched,
heteroaryl, heteroaryl-(C.sub.1 C.sub.6)alkyl in which the alkyl
moiety is linear or branched, heteroaryl-(C.sub.1 C.sub.6)alkenyl
in which the alkenyl moiety is linear or branched, unsubstituted or
substituted linear or branched (C.sub.1 C.sub.6)heterocycloalkyl,
unsubstituted or substituted heterocycloalkenyl, substituted or
unsubstituted heterocycloalkyl-(C.sub.1 C.sub.6)alkyl in which the
alkyl moiety is linear or branched, or substituted or unsubstituted
heterocycloalkenyl-(C.sub.1 C.sub.6)alkyl in which the alkyl moiety
is linear or branched, R represents: a group of formula (V):
##STR00052## wherein Q represents sulphur or oxygen, R' represents
NR'.sub.aR''.sub.a or OR'.sub.a, (wherein Wa and R''a, which may be
the same or different, may take any of the values of R.sub.a and
may also form, together with the nitrogen atom carrying them, a 5-
to 10-membered cyclic group which may contain, in addition to the
nitrogen atom by which it is linked, from one to three hetero atoms
selected from oxygen, sulphur and nitrogen, and R'.sub.a may take
any of the values of R.sub.a except for the hydrogen atom), a group
of formula (VI): ##STR00053## wherein R.sup.2 represents R.sub.a as
defined hereinbefore, R.sup.3 represents COR'.sub.a, CSR'.sub.a,
CONR'.sub.aR''.sub.a, CSNR'.sub.aR''.sub.a, COOR'.sub.a,
CSOR'.sub.a or S(O).sub.vR'.sub.a, wherein R'.sub.a and R''.sub.a,
which may be the same or different, are as defined hereinbefore and
may also form, together with the nitrogen atom carrying them, a
cyclic group as defined hereinbefore, and v is 1 or 2, a group of
formula (VII): ##STR00054## wherein v is as defined hereinbefore
and R.sup.4 represents NR'.sub.aR''.sub.a, NR.sub.aCOR'.sub.a,
NR.sub.aCSR'.sub.a, NR.sub.aCONR'.sub.aR''.sub.a,
NR.sub.aCSNR'.sub.aR''.sub.a or NR.sub.aCOOR'.sub.a, wherein
R.sub.a, R'.sub.a and R''.sub.a are as defined hereinbefore, or
forms, together with two adjacent carbon atoms of the cyclic
structure A carrying it, a 5- to 7-membered ring of formula (VIII):
##STR00055## and wherein the ring of formula (VIII) may be
optionally substituted by one or more radicals, which may be the
same or different, selected from R.sub.a, OR.sub.a, COR.sub.a,
COOR.sub.a, OCOR.sub.a, NR'.sub.aR''.sub.a, NR.sub.aCOR'.sub.a,
CONR'.sub.aR''.sub.a, cyano, oxo, SR.sub.a, S(O)R.sub.a,
SO.sub.2R.sub.a, CSR.sub.a, NR.sub.aCSR'.sub.a,
CSNR'.sub.aR''.sub.a, NR.sub.aCONR'.sub.aR''.sub.a,
NR.sub.aCSNR'.sub.aR''.sub.a and halogen, wherein R.sub.a, R'.sub.a
and R''.sub.a, which may be the same or different, are as defined
hereinbefore and R'.sub.a and R''.sub.a may also form, together
with the nitrogen atom carrying them, a cyclic group as defined
hereinbefore, and R' represents a group of formula (IX): -G-R.sup.5
(IX) wherein G represents an alkylene chain
--(CH.sub.2).sub.t--(wherein t represents an integer from 1 to 4,
optionally substituted by one or more radicals, which may be the
same or different, selected from R.sub.a, OR.sub.a, COOR.sub.a,
COR.sub.a (in which R.sub.a is as defined hereinbefore) or halogen,
and R.sup.5 represents ##STR00056## wherein Q, R.sub.a, R'.sub.a
and R''.sub.a (which may be the same or different) are as defined
hereinbefore, it being possible for R'.sub.a and R''.sub.a to form,
together with the nitrogen atom carrying them, a cyclic group as
defined hereinbefore, it being understood that: "heterocycloalkyl"
may be any saturated mono- or poly-cyclic group containing from 5
to 10 atoms containing from 1 to 3 hetero atoms selected from
nitrogen, oxygen and sulphur, "heterocycloalkenyl" may be any
non-aromatic mono- or poly-cyclic group containing one or more
unsaturations, containing from 5 to 10 atoms and which may contain
from 1 to 3 hetero atoms selected from nitrogen, oxygen and
sulphur, the term "substituted" used with respect to "alkyl",
"alkenyl" and "alkynyl" indicates that such groups are substituted
by one or more radicals, which may be the same or different,
selected from hydroxy, linear or branched (C.sub.1 C.sub.6)alkoxy,
linear or branched (C.sub.1 C.sub.6)alkyl, linear or branched
(C.sub.1 C.sub.6)polyhaloalkyl, amino and halogen, the term
"substituted" used with respect to "cycloalkyl", "cycloalkylalkyl",
"cycloalkenyl", "cycloalkenylalkyl", "heterocycloalkyl",
"heterocycloalkenyl", "hetero-cycloalkylalkyl" and
"heterocycloalkenylalkyl" indicates that the cyclic moiety of such
groups is substituted by one or more radicals, which may be the
same or different, selected from hydroxy, linear or branched
(C.sub.1 C.sub.6)alkoxy, linear or branched (C.sub.1 C.sub.6)alkyl,
linear or branched (C.sub.1 C.sub.6)polyhaloalkyl, amino and
halogen, "aryl" may be any aromatic, mono- or poly-cyclic group
containing from 6 to 22 carbon atoms, and also biphenyl,
"heteroaryl" may be any aromatic mono- or poly-cyclic group
containing from 5 to 10 atoms containing from 1 to 3 hetero atoms
selected from nitrogen, oxygen and sulphur, it being possible for
the "aryl" and "heteroaryl" groups to be substituted by one or more
radicals, which may be the same or different, selected from
hydroxy, linear or branched (C.sub.1 C.sub.6)alkoxy, linear or
branched (C.sub.1 C.sub.6)alkyl, linear or branched (C.sub.1
C.sub.6)polyhaloalkyl, cyano, carboxy, nitro, amino and halogen, it
being understood that: when R.sup.5 represents NHCOR'.sub.a, then R
cannot represent COOR'.sub.a, the compound of formula (I) cannot
represent: N-
{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide, and 25
8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, or an
enantiomer, diastereoisomer, or addition salt thereof with a
pharmaceutically acceptable acid or base.
2. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by R and in the 1- or
2-position by R'.
3. A compound of claim 1, wherein R represents a group of formula
(V).
4. A compound of claim 1, wherein R represents a group of formula
(VI).
5. A compound of claim 1, wherein R represents a group of formula
(VII).
6. A compound of claim 1, wherein R represents a group of formula
(V) wherein Q represents oxygen and R.sup.1 represents
NR'.sub.aR''.sub.a.
7. A compound of claim 1, wherein R represents a group of formula
(V) wherein Q represents oxygen and R.sup.1 represents
OR.sup.1.sub.a.
8. A compound of claim 1, wherein R represents a group of formula
(VI) wherein R.sup.3 represents COR'.sub.a.
9. A compound of claim 1, wherein R represents a group of formula
(VI) wherein R.sup.3 represents COOR'.sub.a.
10. A compound of claim 1, wherein R represents a group of formula
(VII) wherein v is 2 and R.sup.4 represents
NR'.sub.aNR''.sub.a.
11. A compound of claim 1, wherein R' represents G-R.sup.5 wherein
G represents an unsubstituted or substituted alkylene chain
--(CH.sub.2).sub.t--wherein t is 2 or 3 and R.sup.5
##STR00057##
12. A compound of formula (I) according to claim 1, wherein R'
represents G-R.sup.5 wherein G represents an alkylene chain
--(CH.sub.2).sub.t--wherein t is 2 or 3 and R.sup.5 represents
--NHCOR'.sub.a or --CONHR'.sub.a.
13. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by a group of formula
(V) and in the 1- or 2-position by a group of formula (IX).
14. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by a group of formula
(VI) and in the 1- or 2-position by a group of formula (IX).
15. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by a group of formula
(VII) and in the 1- or 2-position by a group of formula (IX).
16. A compound of claim 1, wherein A represents a ring system of
formula (III), which is substituted in the 7-position by a group of
formula --CONR'.sub.aR''.sub.a and substituted in the 1- or
2-position by a group of formula (IX) wherein G represents an
unsubstituted or substituted chain --(CH.sub.2).sub.t--, wherein t
is 2 or 3, and R.sup.5 represents ##STR00058##
17. A compound of claim 1, wherein A represents a ring system of
formula (III), which is substituted in the 7-position by
SO.sub.2NR'.sub.aR'.sub.a and substituted in the 1- or 2-position
by a group of formula (IX) wherein G represents an unsubstituted or
substituted chain --(CH.sub.2).sub.t--, wherein t is 2 or 3, and
R.sup.5 represents ##STR00059##
18. A compound of claim 1, wherein A represents a ring system of
formula (III), which is substituted in the 7-position by a group
--NHCOR'.sub.a and substituted in the 1- or 2-position by a group
of formula (IX) wherein G represents an unsubstituted or
substituted chain --(CH.sub.2).sub.t--, wherein t is 2 or 3, and
R.sup.5 represents ##STR00060##
19. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by a group
--NHCOOR'.sub.a and which is substituted in the 1- or 2-position by
a group of formula (IX) wherein G represents an unsubstituted or
substituted chain --(CH.sub.2).sub.t--, wherein t is 2 or 3, and
R.sup.5 represents ##STR00061##
20. A compound of claim 1, wherein A represents a ring system of
formula (III) substituted in the 7-position by a group
COOR.sup.1.sub.a and which is substituted in the 1- or 2-position
by a group of formula (IX) wherein G represents an unsubstituted or
substituted chain --(CH2).sub.t--, wherein t is 2 or 3, and R.sup.5
represents ##STR00062##
21. A compound of claim 1, wherein A represents naphthalene, which
is optionally substituted (in addition to the substituents R and
R'), in the 3-position.
22. A compound of claim 1, wherein A represents naphthalene, which
is optionally substituted (in addition to the substituents R and
R') in the 3-position, substituted in the 7-position by
--NHCOR.sub.a, SO.sub.2NHR.sub.a, COOR.sup.1.sub.a or CONHR.sub.a,
and substituted in the 1-position by
--(CH.sub.2).sub.t--NHCOR'.sub.a or
--(CH.sub.2).sub.t--CONHR'.sub.a, wherein t is 2 or 3.
23. A compound of claim 1, wherein A represents naphthalene, which
is optionally substituted (in addition to the substituents R and
R') in the 3-position, substituted in the 7-position by
--NHCOOR.sub.a or ##STR00063## wherein alk represents alkyl, and
substituted in the 1-position by --(CH2).sub.t--NHCOR'.sub.a or
--(CH.sub.2).sub.t--CONHR'.sub.a, wherein t is 2 or 3.
24. A compound of claim 1, selected from: N-
{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide, N-(8-
{2-[(2-bromoacetyl)amino]ethyl }-2-naphthyl)-
1-cyclohexanecarboxamide, N-
{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide, and N-
{8-[2-(acetylamino)ethyl]-2-naphthyl }acetamide.
25. A compound of claim 1, selected from: N-ethyl-8-
{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,
N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,
N-phenyl-8-(2-{methyl-[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,
N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naplithamide,
and
N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide.
26. A compound of claim 1, selected from:
N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,
N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide, and
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethylcyclopropanecarboxamide.
27. A compound of claim 1, selected from: ethyl
N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, methyl
N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate, and
methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate.
28. A method for treating a living animal body afflicted with a
disorder of the melatoninergic system selected from anxiety,
insomnia and fatigue due to jetlag, and migraine, comprising the
step of administering to the living animal body an amount of a
compound of claim 1, which is effective for the alleviation of the
disorder.
29. A pharmaceutical composition comprising as active principle an
effective amount of a compound as claimed in claim 1, together with
one or more pharmaceutically acceptable excipients or vehicles.
Description
FIELD OF THE INVENTION
The present invention relates to new substituted cyclic compounds
having very valuable pharmacological characteristics in respect of
melatoninergic receptors.
DESCRIPTION OF THE PRIOR ART
The prior art discloses retroamide chain indoles substituted by
amides or carbamates for use as antagonists of GnRH (WO 9721707)
and amide chain indoles substituted by amides, carbamates or ureas
for use as antihypertensive agents (U.S. Pat. No. 4,803,218).
Retroamide chain benzofuran and benzothiophene compounds
substituted by amides or carbamates have also been described as
anti-inflammatory agents (EP 685475) or inhibitors of bone
resorption.
BACKGROUND OF THE INVENTION
In the last ten years, numerous studies have demonstrated the major
role played by melatonin (5-methoxy-N-acetyltryptamine) in numerous
physiopathological phenomena and also in the control of circadian
rhythm. Its half-life is, however, quite short owing to its being
rapidly metabolised. It is thus very useful to be able to provide
the clinician with melatonin analogues that are metabolically more
stable and that have an agonist or antagonist character on the
basis of which a therapeutic effect that is superior to that of the
hormone itself may be expected.
In addition to their beneficial action on disorders of circadian
rhythm (J. Neurosurg. 1985, 63, pp 321 341) and sleep disorders
(Psychopharmacology, 1990, 100, pp 222 226), ligands of the
melatoninergic system have valuable pharmacological properties in
respect of the central nervous system, especially anxiolytic and
antipsychotic properties (Neuropharmacology of Pineal Secretions,
1990, 8 (3 4), pp 264 272) and analgesic properties
(Pharmacopsychiat., 1987, 20, pp 222 223), and also for the
treatment of Parkinson's disease (J. Neurosurg. 1985, 63, pp 321
341) and Alzheimer's disease (Brain Research, 1990, 528, pp 170
174). Those compounds have also shown activity on certain cancers
(Melatonin--Clinical Perspectives, Oxford University Press, 1988,
pp 164 165), ovulation (Science 1987, 227, pp 714 720), diabetes
(Clinical Endocrinology, 1986, 24, pp 359 364), and in the
treatment of obesity (International Journal of Eating Disorders,
1996, 20 (4), pp 443 446).
Those various effects take place via the intermediary of specific
melatonin receptors. Molecular biology studies have shown the
existence of a number of receptor sub-types that can bind the
hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It
has been possible to locate some of those receptors and to
characterise them for different species, including mammals. In
order to be able to understand the physiological functions of those
receptors better, it is very valuable to have specific ligands
available. Moreover, by interacting selectively with one or other
of those receptors, such compounds can be excellent medicaments for
the clinician in the treatment of pathologies associated with the
melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention
are new, they exhibit very great affinity for melatonin receptors
and/or selectivity for one or other of the melatoninergic receptor
sub-types.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of
formula (I): R-A-R' (I)
wherein .diamond-solid. A represents a ring system of formula
(II):
##STR00002## wherein X represents an oxygen, sulphur or nitrogen
atom or a group C(H).sub.q (wherein q is 0, 1 or 2) or NR.sub.0
(wherein R.sub.0 represents a hydrogen atom, a linear or branched
(C.sub.1 C.sub.6)alkyl group, an aryl group, an aryl-(C.sub.1
C.sub.6)alkyl group in which the alkyl moiety is linear or
branched, or SO.sub.2Ph), Y represents a nitrogen atom or a group
C(H).sub.q (wherein q is 0, 1 or 2), Z represents a nitrogen atom
or a group C(H).sub.q (wherein q is 0, 1 or 2), but X, Y and Z
cannot represent three hetero atoms simultaneously, B represents a
benzene or pyridine nucleus, the symbol means that the bonds may be
single or double, it being understood that the valency of the atoms
is respected. wherein R substitutes the ring B and R' substitutes
the ring containing the groups X, Y and Z, or R and R' substitute
the ring B, a ring system of formula (III):
##STR00003## wherein X' represents an oxygen or sulphur atom or a
group C(H).sub.q (wherein q is 0, 1 or 2), Y' represents a group
C(H).sub.q (wherein q is 0, 1 or 2) or NR.sub.0 wherein R.sub.0 is
as defined hereinbefore, Z' represents a group C(H).sub.q (wherein
q is 0, 1 or 2) or NR.sub.0 wherein R.sub.0 is as defined
hereinbefore, T' represents an oxygen or sulphur atom or a group
C(H).sub.q (wherein q is 0, 1 or 2), it being understood that, when
Y' or Z' represents a hetero atom, the other three variables ((X',
Z', T') and (X', Y', T'), respectively) cannot represent a hetero
atom, the symbol is as defined hereinbefore, B' represents: a
benzene nucleus a naphthalene nucleus when X', Y', Z' and T' do not
simultaneously represent a group C(H).sub.q (wherein q is 0, 1 or
2), or a pyridine nucleus when X' and T' simultaneously represent a
group C(H).sub.q (wherein q is 0, 1 or 2), wherein R substitutes
the ring B' and R' substitutes the ring containing the groups X',
Y', Z' and T', or R and R' substitute the ring B', a ring system of
formula (IV):
##STR00004## representing the ring systems (IV.sub.a-d):
##STR00005## wherein n is an integer such that 0.ltoreq.n.ltoreq.3,
W represents an oxygen, sulphur or nitrogen atom, or a group
[C(H).sub.q].sub.p (wherein q is 0, 1 or 2, and p is 1 or 2) or
NR.sub.0 wherein R.sub.0 is as defined hereinbefore, the symbol is
as defined hereinbefore, wherein R' substitutes the ring
##STR00006## and R substitutes one or other of the two other rings,
or a biphenyl group wherein R substitutes one of the benzene rings
and R' substitutes the other, or R and R' substitute the same
benzene ring, it being understood that the ring systems of formulae
(II), (III) and (IV) and the biphenyl group may be unsubstituted or
substituted (in addition to the substituents R and R') by from 1 to
6 radicals, which may be the same or different, selected from
R.sub.a, OR.sub.a, COR.sub.a, COOR.sub.a, OCOR.sub.a,
OSO.sub.2CF.sub.3 and halogen atoms, wherein R.sub.a represents a
hydrogen atom, an unsubstituted or substituted linear or branched
(C.sub.1 C.sub.6)alkyl group, an unsubstituted or substituted
linear or branched (C.sub.2 C.sub.6)alkenyl group, an unsubstituted
or substituted linear or branched (C.sub.2 C.sub.6)alkynyl group, a
linear or branched (C.sub.1 C.sub.6)polyhaloalkyl group, an
unsubstituted or substituted (C.sub.3 C.sub.8)cycloalkyl group, an
unsubstituted or substituted (C.sub.3 C.sub.8)cycloalkyl-(C.sub.1
C.sub.6)alkyl group in which the alkyl group is linear or branched,
an unsubstituted or substituted (C.sub.3 C.sub.8)cycloalkenyl
group, an unsubstituted or substituted (C.sub.3
C.sub.8)cycloalkenyl-(C.sub.1 C.sub.6)alkyl group in which the
alkyl group is linear or branched, an aryl group, an aryl-(C.sub.1
C.sub.6)alkyl group in which the alkyl moiety is linear or
branched, an aryl-(C.sub.1 C.sub.6)alkenyl group in which the
alkenyl moiety is linear or branched, a heteroaryl group, a
heteroaryl-(C.sub.1 C.sub.6)alkyl group in which the alkyl moiety
is linear or branched, a heteroaryl-(C.sub.1 C.sub.6)alkenyl group
in which the alkenyl moiety is linear or branched, an unsubstituted
or substituted linear or branched (C.sub.1 C.sub.6)heterocycloalkyl
group, an unsubstituted or substituted heterocycloalkenyl group, a
substituted or unsubstituted heterocycloalkyl-(C.sub.1
C.sub.6)alkyl group in which the alkyl moiety is linear or
branched, or a substituted or unsubstituted
heterocycloalkenyl-(C.sub.1 C.sub.6)alkyl group in which the alkyl
moiety is linear or branched, .diamond-solid. R represents: a group
of formula (V):
##STR00007## wherein Q represents a sulphur or oxygen atom, R'
represents a group NR'.sub.aR''.sub.a or OR.sup.1.sub.a (wherein
R'.sub.a and R''.sub.a, which may be the same or different, may
take any of the values of R.sub.a and may also form, together with
the nitrogen atom carrying them, a 5- to 10-membered cyclic group
which may contain, in addition to the nitrogen atom by which it is
linked, from one to three hetero atoms selected from oxygen,
sulphur and nitrogen, and R.sup.1.sub.a may take any of the values
of R.sub.a except for the hydrogen atom), a group of formula
(VI):
##STR00008## wherein R.sup.2 represents a group R.sub.a as defined
hereinbefore, R.sup.3 represents a group COR'.sub.a, CSR'.sub.a,
CONR'.sub.aR''.sub.a, CSNR'.sub.aR''.sub.a, COOR'.sub.a,
CSOR'.sub.a or S(O).sub.vR'.sub.a (wherein R'.sub.a and R''.sub.a,
which may be the same or different, are as defined hereinbefore and
may also form, together with the nitrogen atom carrying them, a
cyclic group as defined hereinbefore, and v is 1 or 2), a group of
formula (VII):
##STR00009## wherein v is as defined hereinbefore and R.sup.4
represents a group NR'.sub.aR''.sub.a, NR.sub.aCOR'.sub.a,
NR.sub.aCSR'.sub.a, NR.sub.aCONR'.sub.aR''.sub.a,
NR.sub.aCSNR'.sub.aR''.sub.a or NR.sub.aCOOR'.sub.a, wherein
R.sub.a, R'.sub.a and R''.sub.a are as defined hereinbefore, or,
when A represents a ring system of formula (II) or (III) or a
biphenyl group, forms, together with two adjacent carbon atoms of
the ring structure A carrying it, a ring of formula (VIII):
##STR00010## the ring formed containing from 5 to 7 atoms and it
being possible for the said ring to contain from 1 to 3 hetero
atoms selected from nitrogen, sulphur and oxygen, and one or more
unsaturations, and being optionally substituted by one or more
radicals, which may be the same or different, selected from
R.sub.a, OR.sub.a, COR.sub.a, COOR.sub.a, OCOR.sub.a,
NR'.sub.aR'.sub.a, NR.sub.aCOR'.sub.a, CONR'.sub.aR''.sub.a, cyano,
oxo, SR.sub.a, S(O)R.sub.a, SO.sub.2R.sub.a, CSR.sub.a,
NR.sub.aCSR'.sub.a, CSNR'.sub.aR''.sub.a,
NR.sub.aCONR'.sub.aR''.sub.a, NR.sub.aCSNR'.sub.aR''.sub.a and
halogen atoms, wherein R.sub.a, R'.sub.a and R''.sub.a, which may
be the same or different, are as defined hereinbefore and R'.sub.a
and R''.sub.a may also form, together with the nitrogen atom
carrying them, a cyclic group as defined hereinbefore,
.diamond-solid. and R' represents a group of formula (IX):
-G-R.sup.5 (IX) wherein G represents an alkylene chain
--(CH.sub.2).sub.t-- (wherein t is an integer such that
0.ltoreq.t.ltoreq.4 when A represents a tricyclic structure and
such that 1.ltoreq.t.ltoreq.4 when A represents a bicyclic
structure), optionally substituted by one or more radicals, which
may be the same or different, selected from R.sub.a, OR.sub.a,
COOR.sub.a, COR.sub.a (in which R.sub.a is as defined hereinbefore)
or halogen atoms, and R.sup.5 represents a group
##STR00011## wherein Q, R.sub.a, R'.sub.a and R''.sub.a (which may
be the same or different) are as defined hereinbefore, it being
possible for R'.sub.a and R''.sub.a to form, together with the
nitrogen atom carrying them, a cyclic group as defined
hereinbefore, it being understood that: "heterocycloalkyl" is taken
to mean any saturated mono- or poly-cyclic group containing from 5
to 10 atoms containing from 1 to 3 hetero atoms selected from
nitrogen, oxygen and sulphur, "heterocycloalkenyl" is taken to mean
any non-aromatic mono- or poly-cyclic group containing one or more
unsaturations, containing from 5 to 10 atoms and which may contain
from 1 to 3 hetero atoms selected from nitrogen, oxygen and
sulphur, the term "substituted" used in respect of the expressions
"alkyl", "alkenyl" and "alkynyl" indicates that the groups in
question are substituted by one or more radicals, which may be the
same or different, selected from hydroxy, linear or branched
(C.sub.1 C.sub.6)alkoxy, linear or branched (C.sub.1 C.sub.6)alkyl,
linear or branched (C.sub.1 C.sub.6)polyhaloalkyl, amino and
halogen atoms, the term "substituted" used in respect of the
expressions "cycloalkyl", "cycloalkylalkyl", "cycloalkenyl",
"cycloalkenylalkyl", "heterocycloalkyl", "heterocycloalkenyl",
"heterocycloalkylalkyl" and "heterocycloalkenylalkyl" indicates
that the cyclic moiety of the groups in question is substituted by
one or more radicals, which may be the same or different, selected
from hydroxy, linear or branched (C.sub.1 C.sub.6)alkoxy, linear or
branched (C.sub.1 C.sub.6)alkyl, linear or branched (C.sub.1
C.sub.6)polyhaloalkyl, amino and halogen atoms, "aryl" is taken to
mean any aromatic, mono- or poly-cyclic group containing from 6 to
22 carbon atoms, and also the biphenyl group, "heteroaryl" is taken
to mean any aromatic mono- or poly-cyclic group containing from 5
to 10 atoms containing from 1 to 3 hetero atoms selected from
nitrogen, oxygen and sulphur, it being possible for the "aryl" and
"heteroaryl" groups to be substituted by one or more radicals,
which may be the same or different, selected from hydroxy, linear
or branched (C.sub.1 C.sub.6)alkoxy, linear or branched (C.sub.1
C.sub.6)alkyl, linear or branched (C.sub.1 C.sub.6)polyhaloalkyl,
cyano, carboxy, nitro, amino and halogen atoms, it being understood
that: when A represents an indole nucleus, there cannot be any
substituents in the 2-position, when A represents an indole nucleus
and R represents a group --NHCOR'.sub.a, --NHCOOR'.sub.a or
NHCONR'.sub.aR''.sub.a, then G-R.sup.5 cannot represent a group
--(CH.sub.2).sub.2--NHCOR.sub.b wherein R.sub.b represents a
(C.sub.1 C.sub.4)alkyl or CF.sub.3 group, when A represents a
benzofuran or benzothiophene nucleus, there cannot be any COPh
groups (wherein Ph is substituted or unsubstituted) in the
2-position, when A represents a benzofuran or benzothiophene
nucleus, R cannot represent a group --NR.sub.aCOR.sub.c,
--NHSO.sub.2R.sub.c, --NHCOCH.sub.2R.sub.c or NHCONHR.sub.c wherein
R.sub.c represents a heterocyclic or aryl group, when A represents
a tetrahydronaphthalene group, R.sup.5 cannot represent a group
CONR'.sub.aR''.sub.a, when A represents a hydrocarbon ring system
and R.sup.5 represents a group NHCOR'.sub.a, then R cannot
represent a group COOR'.sub.a, the compound of formula (I) cannot
represent:
N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide,
N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide,
8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, their
enantiomers and diastereoisomers, and addition salts thereof with a
pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may mentioned,
without implying any limitation, hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic
acid, lactic acid, pyruvic acid, malonic acid, succinic acid,
glutaric acid, fumaric acid, tartaric acid, maleic acid, citric
acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic
acid etc.
Among the pharmaceutically acceptable bases there may mentioned,
without implying any limitation, sodium hydroxide, potassium
hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are those wherein A represents
a ring system of formula (II'):
##STR00012## wherein B, X and the symbol are as defined
hereinbefore, or (III'):
##STR00013## wherein B', T', X' and the symbol are as defined
hereinbefore.
The invention advantageously relates to compounds wherein A
(unsubstituted or substituted by a single substituent (in addition
to R and R') preferably in the 2-position (formula II') or in the
3-position (formula III'), represents a cyclic system of formula
(II'):
##STR00014## wherein B, X and the symbol are as defined
hereinbefore, such as, for example, (dihydro)benzothiophene,
(dihydro)benzofuran, indole, indoline, indan, indene, azaindole,
thienopyridine or furopyridine, or of formula (III'):
##STR00015## wherein B', T', X' and the symbol are as defined
hereinbefore, such as, for example, naphthalene,
tetrahydronaphthalene, (thio)chroman, (dihydro)benzodioxin,
(dihydro)benzoxathiin, (dihydro)benzochromene.
Even more advantageously, the invention relates to compounds
wherein A of formula (II') or (III') is substituted by R in the
5-position (formula II') or 7-position (formula III') and by R' in
the 3-position (formula II') or 1- or 2-position (formula
III').
Preferred substituents R of the invention are those represented by
a group of formula (V), (VI) or (VII).
More advantageously, preferred substituents R of the invention are
those represented by a group of formula (V) wherein Q represents an
oxygen atom and R.sup.1 represents a group NR'.sub.aR''.sub.a
(wherein R'.sub.a and R''.sub.a are as defined hereinbefore) or
OR.sup.1.sub.a (wherein R.sup.1.sub.a is as defined
hereinbefore),
a group of formula (VI) wherein R.sup.3 represents a group
COR'.sub.a or COOR'.sub.a (wherein R'.sub.a is as defined
hereinbefore),
or a group of formula (VII) wherein v is 2 and R.sup.4 represents a
group NR'.sub.aR''.sub.a as defined hereinbefore.
Even more advantageously, preferred substituents R of the invention
are those represented by a group CONR'.sub.aR''.sub.a or
SO.sub.2NR'.sub.aR''.sub.a wherein R'.sub.a and R''.sub.a, which
may be the same or different, represent a hydrogen atom or an
alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or
heteroarylalkyl group, such as, for example, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl,
naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cyclohexenyl, methylcyclopropyl, ethylcyclopropyl,
furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl, or form,
together with the nitrogen atom carrying them, a piperazine,
piperidine, morpholine or thiomorpholine group, or by a group
NCOR'.sub.a, NCOOR'.sub.a or COOR.sup.1.sub.a wherein R'.sub.a
represents a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl
group, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl,
phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl,
pyridyl, furylmethyl, pyridylmethyl, and R.sup.1.sub.a represents
an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl or heteroarylalkyl group, such as, for
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl,
vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl,
furylmethyl, pyridylmethyl.
Preferred substituents R' of the invention are those wherein G
represents an unsubstituted or substituted alkylene chain
--(CH.sub.2).sub.t--, wherein t is 2 or 3, and R.sup.5 represents a
group
##STR00016## wherein R.sub.a, R'.sub.a, R''.sub.a and Q are as
defined hereinbefore.
Even more advantageously, preferred substituents R' of the
invention are those wherein G represents a group
--(CH.sub.2).sub.t--, wherein t is 2 or 3, and R.sup.5 represents a
group
##STR00017## wherein R'.sub.a represents an alkyl, polyhaloalkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl,
cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl
group, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl,
phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl,
pyridyl, furylmethyl, pyridylmethyl, or G represents a group
--(CH.sub.2).sub.3-- and R.sup.5 represents a group
##STR00018## wherein R.sub.a represents an alkyl, polyhaloalkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl,
cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl
group, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl,
phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl,
pyridyl, furylmethyl, pyridylmethyl.
More especially, preferred compounds of the invention are those
wherein A represents a ring system of formula (II') or (III') and R
represents a group of formula (V), (VI) or (VII).
More advantageously, the invention relates to compounds
wherein:
A represents a group of formula (II') or (III') substituted in the
5-position (formula II') or 7-position (formula III') by R and in
the 3-position (formula II') or 1- or 2-position (formula III') by
R',
and R represents a group CONR'.sub.aR''.sub.a,
SO.sub.2NR'.sub.aR''.sub.a, COOR.sup.1.sub.a, NHCOR'.sub.a or
NHCOOR'.sub.a (wherein R'.sub.a, R.sup.1.sub.a and R'.sub.a are as
defined hereinbefore).
Even more advantageously, preferred compounds of the invention are
those wherein A represents a ring system of formula (II') or (III')
optionally substituted (in addition to R and R') by a substituent
in the 2-position (formula II') or 3-position (formula III'),
substituted in the 5-position (formula II') or 7-position (formula
III') by R and in the 3-position (formula II') or 1- or 2-position
(formula III') by R',
R represents a group CONR'.sub.aR''.sub.a,
SO.sub.2NR'.sub.aR''.sub.a, COOR'.sub.a, NHCOR'.sub.a or
NHCOOR'.sub.a (wherein R'.sub.a, R''.sub.a and R.sup.1.sub.a are as
defined hereinbefore),
and R' is such that G represents an unsubstituted or substituted
alkylene chain --(CH.sub.2).sub.t--, wherein t is 2 or 3, and
R.sup.5 represents a group
##STR00019## wherein R.sub.a, R'.sub.a, R''.sub.a and Q are as
defined hereinbefore.
Even more especially, the invention relates to
(dihydro)benzothiophenes, (dihydro)benzofurans, indoles, indolines,
indenes, indans, azaindoles, thieno- or furopyridines optionally
substituted in the 2-position, and to dihydronaphthalenes,
tetrahydronaphthalenes, naphthalenes or chromans optionally
substituted in the 3-position,
substituted in the 5-position (or 7-position, respectively) by a
group CONR'.sub.aR''.sub.a, SO.sub.2NR'.sub.aR''.sub.a,
COOR.sup.1.sub.a, NHCOR'.sub.a or NHCOOR'.sub.a wherein R'.sub.a
and R'.sub.a, which may be the same or different, represent a
hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl,
arylalkyl, heteroaryl or heteroarylalkyl group, such as, for
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl,
vinyl, allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
methylcyclopropyl, ethylcyclopropyl, furyl, thienyl, pyridyl,
furylmethyl, pyridylmethyl, or R'.sub.a and R''.sub.a form,
together with the nitrogen atom carrying them, a piperazine,
piperidine, morpholine or thiomorpholine group, and R.sup.1.sub.a
represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl,
heteroaryl or heteroarylalkyl group, such as, for example, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,
phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,
ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl,
pyridylmethyl,
and substituted in the 3-position (or 1- or 2-position,
respectively) by a group --(CH.sub.2).sub.t--NHCOR'.sub.a wherein t
is 2 or 3 and R'.sub.a represents an alkyl, polyhaloalkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl,
cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl
group, such as, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl, benzyl,
phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl,
pyridyl, furylmethyl, pyridylmethyl.
Even more advantageously, preferred compounds of the invention
are:
naphthalenes, dihydronaphthalenes or tetrahydronaphthalenes
optionally substituted in the 3-postion, substituted in the
7-position by a group NHCOR.sub.a, NHCOOR.sub.a, CONHR.sub.a or
COOR.sup.1.sub.a (wherein R.sub.a and R.sup.1.sub.a are as defined
hereinbefore) and substituted in the 1-position by a group
--(CH.sub.2).sub.t--NHCOR'.sub.a wherein t is 2 or 3 and R'.sub.a
is as defined hereinbefore,
or benzofurans or benzothiophenes optionally substituted in the
2-position, substituted in the 5-postion by a group NHCOR.sub.a,
NHCOOR.sub.a, CONHR.sub.a or COOR.sup.1.sub.a (wherein R.sub.a and
R.sup.1.sub.a are as defined hereinbefore) and substituted in the
3-position by a group --(CH.sub.2).sub.t--NHCOR'.sub.a wherein t is
2 or 3 and R'.sub.a is as defined hereinbefore.
The invention relates very particularly to the compounds of formula
(I) that are
N-{2-[6-(acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide,
methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate,
methyl
3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,
methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate-
, methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate,
N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide,
3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide,
3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxami-
de, 3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxami-
de, 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxami-
de, 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,
3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide-
,
N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiop-
hene-5-carboxamide,
N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide,
N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide,
N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide,
N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide,
N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide-
, N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide,
N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide,
N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,
N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,
N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,
N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide,
N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide,
N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,
N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide,
N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropanecarboxamide-
,
N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide,
N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide,
N-(2-{5-[(cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)benzamide,
N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide,
N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarb-
oxamide,
N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}et-
hyl)acetamide,
N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropa-
ne-carboxamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acet-
amide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethy-
l)cyclopropane-carboxamide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)benz-
amide,
N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethy-
l)-2-furamide, methyl
N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate, methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,
tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate,
tert-butyl
3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate,
methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate,
methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate,
methyl
5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate,
methyl
3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate,
ethyl 3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate,
methyl
3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,
methyl
3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate-
, methyl
3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate-
, methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin--
5-yl-carbamate, ethyl
N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, methyl
N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate, hexyl
N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate,
methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate, methyl
3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate, methyl
3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,
methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate, methyl
3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate,
3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide.
The enantiomers and diastereoisomers, as well as the addition salts
with a pharmaceutically acceptable acid or base, of the preferred
compounds of the invention form an integral part of the
invention.
The invention relates also to a process for the preparation of
compounds of formula (I), which process is characterised in that
there is used as starting material the compound of formula (X)
##STR00020## wherein A and R' are as defined hereinbefore, which is
subjected to demethylation using conventional agents such as HBr,
AlCl.sub.3, AlBr.sub.3, BBr.sub.3 or Lewis acid/nucleophile binary
systems such as AlCl.sub.3/PhCH.sub.2SH, or BBr.sub.3/Me.sub.2S,
for example, to obtain the compound of formula (XI): HO-A-R' (XI)
wherein A and R' are as defined hereinbefore, .diamond-solid. which
is converted, by means of the action of reagents such as
POCl.sub.3, PCl.sub.5, Ph.sub.3PBr.sub.2, PhPCl.sub.4, HBr or HI,
into the corresponding halogenated compound of formula (XII):
Hal-A-R' (XII) wherein A and R' are as defined hereinbefore and Hal
represents a halogen atom (which compounds of formula (XII) can be
obtained by exchange reactions such as, for example, the treatment
of a chlorinated compound with KF in dimethylformamide to yield the
corresponding fluorinated compound or the treatment of a brominated
compound with KI in the presence of copper salts to yield the
corresponding iodinated compound), which is treated: with carbon
monoxide and Bu.sub.3SnH, the reaction being catalysed with
palladium(0), to yield the corresponding aldehyde of formula
(XIII):
##STR00021## wherein A and R' are as defined hereinbefore, which
compound of formula (XIII) may alternatively be obtained by
customary lithiation methods starting from the halogenated compound
of formula (XII), or via the corresponding vinyl compound (obtained
starting from the compound of formula (XII) by the action of
vinyltributyltin and tetrakis palladium) subjected to ozonolysis,
or furthermore by direct formylation of the nucleus A, for example
according to a Vilsmeier reaction, which compound of formula (XIII)
is subjected to an oxidising agent to obtain the compound of
formula (XIV): HOOC-A-R' (XIV) wherein A and R' are as defined
hereinbefore, which is: either subjected, in the presence of an
acid catalyst, to the action of an alcohol of formula
R.sup.1.sub.aOH, wherein R.sup.1.sub.a is as defined hereinbefore,
to yield the compound of formula (I/a), a particular case of the
compounds of formula (I):
##STR00022## wherein A, R.sup.1.sub.a and R' are as defined
hereinbefore, which may be subjected to a thionating agent, such as
Lawesson's reagent, for example, to yield the compound of formula
(I/b), a particular case of the compounds of formula (I):
##STR00023## wherein A, R.sup.1.sub.a and R' are as defined
hereinbefore, or converted, after the action of thionyl chloride
and an azide, and then of an acid, into the compound of formula
(XV): H.sub.2N-A-R' (XV) wherein A and R' are as defined
hereinbefore, with which there is condensed: either an acyl
chloride ClCOR.sub.a or the corresponding anhydride (mixed or
symmetrical), wherein R.sub.a is as defined hereinbefore, to yield
the compound of formula (I/c), a particular case of the compounds
of formula (I):
##STR00024## wherein R.sub.a, A and R' are as defined hereinbefore,
which may be subjected to the action of a compound of formula
(XVI): R.sup.1.sub.a-J (XVI) wherein R.sup.1.sub.a is as defined
hereinbefore and J represents a leaving group such as a halogen
atom or a tosyl group, to obtain the compound of formula (I/d), a
particular case of the compounds of formula (I):
##STR00025## wherein R.sub.a, R.sup.1.sub.a, A and R' are as
defined hereinbefore, which compounds of formulae (I/c) and (I/d)
constitute the compound of formula (I/e), a particular case of the
compounds of formula (I):
##STR00026## wherein R.sub.a, R'.sub.a, A and R' are as defined
hereinbefore, which compound of formula (I/e) may be subjected to a
thionating agent, such as Lawesson's reagent, for example, to
obtain the compound of formula (I/f), a particular case of the
compounds of formula (I):
##STR00027## wherein R.sub.a, R'.sub.a, A and R' are as defined
hereinbefore, or a compound of formula (XVII): Q=C.dbd.N--R'.sub.a
(XVII) wherein Q and R'.sub.a are as defined hereinbefore, to yield
the compound of formula (I/g), a particular case of the compounds
of formula (I):
##STR00028## wherein R'.sub.a, Q, A and R' are as defined
hereinbefore, which may be subjected to the action of a compound of
formula (XVI) to obtain the compound of formula (I/h), a particular
case of the compounds of formula (I):
##STR00029## wherein Q, R.sup.1.sub.a, A and R' are as defined
hereinbefore and R.sup.2.sub.a and R'.sup.2.sub.a, which may be the
same or different, may take any of the values of R.sub.a except for
the hydrogen atom and cannot form a cyclic structure together with
the nitrogen atom carrying them, or a compound of formula
(XVIII):
##STR00030## wherein R'.sub.a is as defined hereinbefore, or its
corresponding anhydride (R'.sub.aOCO).sub.2O, to obtain the
compound of formula (I/i), a particular case of the compounds of
formula (I):
##STR00031## wherein R'.sub.a, A et R' are as defined hereinbefore,
which may be subjected to the action of a compound of formula (XVI)
and/or the action of a thionating agent to yield the compound of
formula (I/j), a particular case of the compounds of formula
(I):
##STR00032## wherein R.sub.a, R'.sub.a, Q, A and R' are as defined
hereinbefore, or a compound of formula (XIX): R.sub.aSO.sub.2Cl
(XIX) wherein R.sub.a is as defined hereinbefore, optionally
followed by the action of a compound of formula (XVI) to yield the
compound of formula (I/k), a particular case of the compounds of
formula (I):
##STR00033## wherein R.sub.a, A and R' are as defined hereinbefore,
.diamond-solid. or which compound of formula (XI) is converted, by
means of the action of benzylthiol and trifluoromethanesulphonic
acid, into the corresponding benzylthio compound of formula (XX):
Ph-CH.sub.2--S-A-R' (XX) wherein A and R' are as defined
hereinbefore, which is placed in the presence of iodosobenzene and
hydrochloric acid to yield the compound of formula (XXI):
ClSO.sub.2-A-R' (XXI) wherein A and R' are as defined hereinbefore,
with which there is condensed an amine R'.sub.aR''.sub.aNH (wherein
R'.sub.a and R''.sub.a are as defined hereinbefore), to obtain the
compound of formula (I/l), a particular case of the compounds of
formula (I): R'.sub.aR''.sub.aNSO.sub.2-A-R' (I/l)
wherein R'.sub.a, R''.sub.a, A and R' are as defined
hereinbefore,
it being possible for the compound of formula (I/la), a particular
case of the compounds of formula (I/l): H.sub.2NSO.sub.2-A-R'
(I/la) wherein A and R' are as defined hereinbefore, to be
subjected to the action of an acyl chloride ClCOR'.sub.a,
optionally followed by the action of a compound of formula (XVI)
and/or Lawesson's reagent, to yield the compound of formula (I/m),
a particular case of the compounds of formula (I):
##STR00034## wherein R.sub.a, R'.sub.a, Q, A and R' are as defined
hereinbefore, of a compound of formula (XVII), optionally followed
by the action of a compound of formula (XVI) to obtain the compound
of formula (I/n), a particular case of the compounds of formula
(I):
##STR00035## wherein R.sub.a, R'.sub.a, R''.sub.a, Q, A and R' are
as defined hereinbefore, or of a compound of formula (XVIII),
optionally followed by the action of a compound of formula (XVI),
to yield the compound of formula (I/o), a particular case of the
compounds of formula (I):
##STR00036## wherein R.sub.a, R'.sub.a, A and R' are as defined
hereinbefore, which compounds (I/a) to (I/o) can be purified in
accordance with a conventional separation technique, are converted,
if desired, into their addition salts with a pharmaceutically
acceptable acid or base and, optionally, are separated into their
isomers in accordance with a conventional separation technique.
The starting compounds (X) are either commercially available or are
described in the literature, for example in the Patent Applications
EP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586,
EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685,
or W09738682.
Another advantageous process of the invention relating to
preparation of the compounds of formula (I) is characterised in
that there is used as starting material the compound of formula
(XXII):
##STR00037## wherein R and the symbol are as defined hereinbefore,
Y'' represents a group C(H).sub.q (wherein q is 0, 1 or 2) or a
bond, and X'' represents an oxygen, nitrogen or sulphur atom or a
group C(H).sub.q (wherein q is 0, 1 or 2) or NR.sub.0 (wherein
R.sub.0 is as defined hereinbefore), it being understood that when
X'' represents a nitrogen atom or a group NR.sub.0 then Y''
represents a bond, which is subjected to a Wittig reaction and then
to reduction to yield the compound of formula (XXIII):
##STR00038## wherein R, X'', Y'', G and the symbol are as defined
hereinbefore, which may be oxidised to yield the compound of
formula (XXIV):
##STR00039## wherein R.sup.1, X'', Y'', G and the symbol are as
defined hereinbefore,
which is: either hydrolysed in an acid or basic medium and then
subjected, after activation to the acid chloride form or in the
presence of a coupling agent, to the action of an amine
HNR'.sub.aR''.sub.a wherein R'.sub.a and R''.sub.a are as defined
hereinbefore to yield the compound of formula (I/p), a particular
case of the compounds of formula (I):
##STR00040## wherein R, X'', Y'', G, R'.sub.a, R''.sub.a and the
symbol are as defined hereinbefore, which may be subjected to a
thionating agent such as Lawesson's reagent to yield the compound
of formula (I/q), a particular case of the compounds of formula
(I):
##STR00041## wherein R, X'', Y'', G, R'.sub.a, R''.sub.a and the
symbol are as defined hereinbefore, or hydrolysed in an acid or
basic medium and then converted into the corresponding azide to
yield, after having been subjected to a Curtius rearrangement and
hydrolysis, the compound of formula (XXV):
##STR00042## wherein R, X'', Y''and G are as defined hereinbefore,
which is reacted with an acyl chloride ClCOR'.sub.a or the
corresponding anhydride (mixed or symmetrical) wherein R'.sub.a is
as defined hereinbefore, optionally followed by the action of a
compound of formula (XVI) and/or the action of a thionating agent
to yield the compound of formula (I/r), a particular case of the
compounds of formula (I):
##STR00043## wherein R. X'', Y'', G, R.sub.a, R'.sub.a, Q and the
symbol are as defined hereinbefore, or with a compound of formula
(XVII), optionally followed by the action of a compound of formula
(XVI) to yield the compound of formula (I/s), a particular case of
the compounds of formula (I):
##STR00044## wherein R, X'', Y'', G, R.sub.a, R'.sub.a, R''.sub.a,
Q and the symbol are as defined hereinbefore, which compounds (I/p)
to (I/s) can be purified in accordance with a conventional
separation technique, are converted, if desired, into their
addition salts with a pharmaceutically acceptable acid or base and,
optionally, are separated into their isomers in accordance with a
conventional separation technique.
The compounds of formula (XXII) are either commercially available
or easily accessible to the person skilled in the art, starting
from the compound of formula (XXVI):
##STR00045## wherein R is as defined hereinbefore and X'''
represents an oxygen or sulphur atom or a group NR.sub.0 (wherein
R.sub.0 is as defined hereinbefore), (the compound of formula
(XXVI) either being commercially available or being obtained
starting from the compound of formula (XXVI'):
##STR00046## wherein X''' is as defined hereinbefore, by
conventional reactions for substitution of the aromatic nucleus),
which is subjected to the action of AlCl.sub.3 to yield the
compound of formula (XXVII):
##STR00047## wherein R and X''' are as defined hereinbefore, which
is subjected to bromination to obtain the compound of formula
(XXVIII):
##STR00048## wherein X''' and R are as defined hereinbefore, which
is placed in a basic medium to yield the compound of formula
(XXIX), a particular case of the compounds of formula (XXII):
##STR00049## wherein R and X''' are as defined hereinbefore, or
starting from the compound of formula (XXX):
##STR00050## wherein R, X'', Y'' and the symbol are as defined
hereinbefore, which is cyclised in the presence of polyphosphoric
acid to yield the compound of formula (XXII).
The invention relates also to a process for the preparation of
compounds of formula (I) wherein R represents a ring of formula
(VIII), which process is characterised in that compounds of
formulae (I/a) to (I/s) are used as starting materials, which are
cyclised according to methods described in the literature, for
example in the Patent Applications EP0708099 or WO09732871.
The compounds of the invention and pharmaceutical compositions
comprising them are proving to be useful in the treatment of
disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact
shown them to be non-toxic, to have strong affinity for melatonin
receptors and to possess important activities in respect of the
central nervous system and, in particular, there have been found
therapeutic properties in relation to sleep disorders, anxiolytic,
antipsychotic and analgesic properties and in relation to the
microcirculation, enabling it to be established that the products
of the invention are useful in the treatment of stress, sleep
disorders, anxiety, seasonal affective disorder, cardiovascular
pathologies, pathologies of the digestive system, insomnia and
fatigue resulting from jet lag, schizophrenia, panic attacks,
melancholia, appetite disorders, obesity, insomnia, psychotic
disorders, epilepsy, diabetes, Parkinson's disease, senile
dementia, various disorders associated with normal or pathological
ageing, migraine, memory loss, Alzheimer's disease, and also
cerebral circulation disorders. In another field of activity, it
appears that, in treatment, the products of the invention can be
used in sexual dysfunction, that they have ovulation-inhibiting
properties and immunomodulating properties and are able to be used
in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal
affective disorder, sleep disorders, cardiovascular pathologies,
insomnia and fatigue resulting from jet lag, appetite disorders and
obesity.
For example, the compounds will be used in the treatment of
seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions
comprising at least one compound of formula (I), alone or in
combination with one or more pharmaceutically acceptable
excipients.
Among the pharmaceutical compositions according to the invention
there may be mentioned more especially those that are suitable for
oral, parenteral, nasal, per- or trans-cutaneous, rectal,
perlingual, ocular or respiratory administration and especially
tablets, dragees, sublingual tablets, sachets, paquets, gelatin
capsules, glossettes, lozenges, suppositories, creams, ointments,
dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the
patient, the route of administration, the nature of the therapeutic
indication, or possible associated treatments, and ranges from 0.01
mg to 1 g per 24 hours in 1 or more administrations.
The following Examples illustrate the invention but do not limit it
in any way. The following Preparations yield compounds of the
invention or synthesis intermediates that are useful in preparation
of the compounds of the invention.
Preparation 1
N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide
Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethyl
sulphide complex are dissolved in 100 ml of dichloromethane and
stirred for 15 min at ambient temperature. A solution of 13.7 mmol
of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of
dichloromethane is added and the reaction mixture is heated at
reflux for 30 hours. After cooling, the reaction mixture is
hydrolysed with caution and the dichloromethane is evaporated off.
The mixture is then extracted with ethyl acetate, the combined
organic phases are washed with a 1M aqueous solution of potassium
bicarbonate and then with 1M sodium hydroxide solution. The organic
phase is dried over magnesium sulphate and concentrated to yield
the title compound.
Preparation 2
N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-phenylacetamide
The procedure is as in Preparation 1, but the
N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by
N-[2-(7-methoxy-1-naphthyl)ethyl]-2-phenylacetamide.
In Preparations 3 to 37, the procedure is as in Preparation 1, but
the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by the
appropriate methoxylated starting substrate.
Preparation 3
N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-bromoacetamide
Preparation 4
N-[2-(8-Hexyl-7-hydroxy-1-naphthyl)ethyl]-2-phenylacetamide
Preparation 5
N-Cyclopropylmethyl-2-(7-hydroxy-1-naphthyl)acetamide
Preparation 6
N-Cyclohexyl-4-(7-hydroxy-1-naphthyl)butanamide
Preparation 7
N-[2-(7-Hydroxy-1-naphthyl)ethyl]-N-methyl-N'-propylurea
Preparation 8
N-[3-(7-Hydroxy-1-naphthyl)propyl]acetamide
Preparation 9
N-[2-(7-Hydroxy-1-naphthyl)ethyl]-3-butenamide
Preparation 10
N-[3-(7-Hydroxy-1-naphthyl)propyl]-1-cyclohexanecarboxamide
Preparation 11
N-[2-(2-Hydroxy-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide
Preparation 12
N-[2-(2-Hydroxy-1-naphthyl)-1-methylethyl]propanamide
Preparation 13
N-[2-(7-Hydroxy-3-phenyl-1-naphthyl)ethyl]acetamide
Preparation 14
N-[2-(3-Benzoyl-7-hydroxy-1-naphthyl)ethyl]-N'-propylurea
Preparation 15
N-{2-13-(Cyclopropylmethyl)-7-hydroxy-1-naphthyl]ethyl}acetamide
Preparation 16
N-[3-(5-Hydroxybenzo[b]furan-3-yl)propyl]acetamide
Preparation 17
N-Methyl-4-(5-hydroxybenzo[b]furan-3-yl)butanamide
Preparation 18
N-[2-(5-Hydroxybenzo[b]furan-3-yl)ethyl]acetamide
Preparation 19
N-[(2-Benzyl-5-hydroxybenzo[b]thiophen-3-yl)methyl]acetamide
Preparation 20
N-[2-(5-Hydroxythieno[3,2-b]pyridin-3-yl)ethyl]acetamide
Preparation 21
N-[2-(5-Hydroxy-1H-3-indolyl)ethyl]benzamide
Preparation 22
N-{2-[2-(4-Fluorobenzyl)-5-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-
ethyl}acetamide
Preparation 23
N-[2-(2-Benzyl-5-hydroxybenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxami-
de
Preparation 24
N-[(6-Hydroxy-3,4-dihydro-2H-3-chromenyl)methyl]acetamide
Preparation 25
N-[2-(6-Hydroxy-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide
Preparation 26
N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]acetamide
Preparation 27
N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]butanamide
Preparation 28
N-[2-(6-Hydroxy-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide
Preparation 29
N-[2-(7-Hydroxy-1,4-benzodioxin-2-yl)ethyl-N'-propylurea
Preparation 30
N-[2-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]acetamide
Preparation 31
N-[2-(6-Hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide
Preparation 32
N-[(9-Hydroxy-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylace-
tamide
Preparation 33
N-Cyclopropyl-N'-(4-hydroxy-2,3-dihydro-1H-2-phenalenyl)thiourea
Preparation 34
N-Cyclobutyl-3-hydroxy-4,5-dihydro-3H-benzo
[cd]isobenzofuran-4-carboxamide
Preparation 35
N-{2-[7-Hydroxy-3-naphthyl-1-naphthyl]ethyl}heptanamide
Preparation 36
N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
Preparation 37
N-[2-(6-Hydroxy-2,3-dihydro-1H-1-indenyl)ethyl]acetamide
Preparation 38
N-Cyclohexyl-4-(7-chloro-1-naphthyl)butanamide
Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at a
flow rate such that the reaction temperature is maintained between
70 and 80.degree. C. After all the chlorine has been added, the
phenylphosphine tetrachloride so obtained is a pale yellow liquid.
10 mmol of the product obtained in Preparation 5 are added all at
once and the reaction mixture is heated at 160.degree. C.
overnight. After cooling, the solution is poured into a water/ice
mixture (20 ml) and is neutralised with a 50% aqueous solution of
sodium hydroxide. After extraction with ether, the organic phases
are dried and concentrated under reduced pressure to yield a
residue, which is chromatographed on silica gel to obtain the pure
title product.
In Preparation 39, the procedure is as in Preparation 38, but the
appropriate starting compound is used.
Preparation 39
N-[(6-Chloro-3,4-dihydro-2H-3-chromenyl)methyl]acetamide
Starting compound: Preparation 24
Preparation 40
N-[2-(7-Bromo-1-naphthyl)ethyl]-2-phenylacetamide
Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured
into a 150 ml three-necked flask equipped with a bromine funnel, a
condenser surmounted by a tube filled with calcium chloride and a
mechanical stirrer. The solution is cooled with the aid of an ice
bath, with stirring, and bromine is added (10 mmol). At the end of
the addition, the ice bath is removed and the product obtained in
Preparation 2 (8 mmol) is then added. The reaction mixture is
stirred at 60 70.degree. C. until the starting compound has
disappeared (monitored by TLC). At the end of the reaction, the
mixture is filtered and the filtrate is then concentrated under
reduced pressure. The residue is taken up in ethyl acetate, washed
with water and then with saturated potassium hydrogen carbonate
solution and once again with water, and is then dried over
magnesium sulphate and concentrated under reduced pressure. The
residue is filtered through silica gel to yield the title
product.
In Preparations 41 to 72.1, the procedure is as in Preparation 40,
starting from the appropriate reactant.
Preparation 41
N-Cyclopropylmethyl-2-(7-bromo-1-naphthyl)acetamide
Starting compound: Preparation 5
Preparation 42
N-[2-(7-Bromo-1-naphthyl)ethyl]-N-methyl-N'-propylurea
Starting compound: Preparation 7
Preparation 43
N-[3-(7-Bromo-1-naphthyl)propyl]-1-cyclohexanecarboxamide
Starting compound: Preparation 10
Preparation 44
N-[2-(2-Bromo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide
Starting compound: Preparation 11
Preparation 45
N-[2-(3-Benzoyl-7-bromo-1-naphthyl)ethyl]-N'-propylurea
Starting compound: Preparation 14
Preparation 46
N-[3-(5-Bromobenzo[b]furan-3-yl)propyl]acetamide
Starting compound: Preparation 16
Preparation 47
N-[(2-Benzyl-5-bromobenzo[b]thiophen-3-yI)methyl]acetamide
Starting compound: Preparation 19
Preparation 48
N-[2-(5-Bromo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3yl)eth-
yl]acetamide
Starting compound: Preparation 22
Preparation 49
N-[2-(6-Bromo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide
Starting compound: Preparation 25
Preparation 50
N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]acetamide
Starting compound: Preparation 26
Preparation 51
N-[2-(6-Bromo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide
Starting compound: Preparation 28
Preparation 52
N-[2-(7-Bromo-1,4-benzodioxin-2-yl)ethyl]-N'-propylurea
Starting compound: Preparation 29
Preparation 53
N-[2-(6-Bromo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide
Starting compound: Preparation 31
Preparation 54
N-[(9-Bromo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylaceta-
mide
Starting compound: Preparation 32
Preparation 55
N-(4-Bromo-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea
Starting compound: Preparation 33
Preparation 56
N-Cyclobutyl-6-bromo-4,5-dihydro-3H-benzo
[cd]isobenzofuran-4-carboxamide
Starting compound: Preparation 34
Preparation 57
N-[2-(7-Bromo-3-naphthyl-1-naphthyl)ethyl]heptanamide
Starting compound: Preparation 35
Preparation 58
N-[2-(7-Bromo-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 1
Preparation 59
N-[2-(7-Bromo-1-naphthyl)ethyl]-3-butenamide
Starting compound: Preparation 9
Preparation 60
N-[2-(7-Bromo-1-naphthyl)ethyl]-2-bromoacetamide
Starting compound: Preparation 3
Preparation 61
N-[2-(7-Bromo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide
Starting compound: Preparation 4
Preparation 62
N-[3-(7-Bromo-1-naphthyl)propyl]acetamide
Starting compound: Preparation 8
Preparation 63
N-[2-(2-Bromo-1-naphthyl)-1-methylethyl]propanamide
Starting compound: Preparation 12
Preparation 64
N-{2-[7-Bromo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide
Starting compound: Preparation 15
Preparation 65
N-Methyl-3-(5-bromobenzo[b]furan-3-yl)butanamide
Starting compound: Preparation 17
Preparation 66
N-[2-(5-Bromothieno[3,2-b]pyridin-3-yl)ethyl]acetamide
Starting compound: Preparation 20
Preparation 67
N-[2-(5-Bromo-1H-3-indolyl)ethyl]benzamide
Starting compound: Preparation 21
Preparation 68
N-[2-(2-Benzyl-5-bromobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide
Starting compound: Preparation 23
Preparation 69
N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]butanamide
Starting compound: Preparation 27
Preparation 70
N-[2-(6-Bromo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide
Starting compound: Preparation 37
Preparation 71
N-[2-(7-Bromo-3-phenyl-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 13
Preparation 72
N-[2-(5-Bromobenzo[b]furan-3-yl)ethyl]acetamide
Starting compound: Preparation 18
Preparation 72.1
N-[2-7-Bromo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 36
Preparation 73
N-[2-(7-Iodo-1-naphthyl)ethyl]-2-phenylacetamide
A mixture of the product obtained in Preparation 40 (2 mmol),
potassium iodide (30 mmol) and copper(I) iodide (10 mmol) in
hexamethylphosphoramide (6 ml) is heated at 150 160.degree. C.,
with stirring, under a nitrogen atmosphere until 90% conversion has
been achieved (monitored by TLC). Then, dilute hydrochloric acid,
and then ether, are added and the mixture is then filtered to
remove the insoluble copper(I) salts. The organic phase is
separated off, washed with sodium sulphite solution and with water,
dried over magnesium sulphate and evaporated to yield a residue
which is chromatographed on silica gel to yield the title
product.
In Preparations 74 to 108 the procedure is as in Preparation 73,
but the product of Preparation 40 is replaced by the appropriate
substrate.
Preparation 74
N-Cyclopropylmethyl-2-(7-iodo-1-naphthyl)acetamide
Starting compound: Preparation 41
Preparation 75
N-[2-(7-Iodo-1-naphthyl)ethyl]-N-methyl-N'-propylurea
Starting compound: Preparation 42
Preparation 76
N-[3-(7-Iodo-1-naphthyl)propyl]-1-cyclohexanecarboxamide
Starting compound: Preparation 43
Preparation 77
N-[2-(2-Iodo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide
Starting compound: Preparation 44
Preparation 78
N-[2-(3-Benzoyl-7-iodo-1-naphthyl)ethyl]-N'-propylurea
Starting compound: Preparation 45
Preparation 79
N-[3-(5-Iodobenzo[b]furan-3-yl)propyl]acetamide
Starting compound: Preparation 46
Preparation 80
N-[(2-Benzyl-5-iodobenzo[b]thiophen-3-yl)methyl]acetamide
Starting compound: Preparation 47
Preparation 81
N-[2-(5-Iodo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-et-
hyl]acetamide
Starting compound: Preparation 48
Preparation 82
N-[(6-Iodo-3,4-dihydro-2H-3-chromenyl)methyl]acetamide
Starting compound: Preparation 39
Preparation 83
N-[2-(6-Iodo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide
Starting compound: Preparation 49
Preparation 84
N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]acetamide
Starting compound: Preparation 50
Preparation 85
N-[2-(6-Iodo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide
Starting compound: Preparation 51
Preparation 86
N-[2-(7-Iodo-1,4-benzodioxin-2-yl)ethyl]-N'-propylurea
Starting compound: Preparation 52
Preparation 87
N-[2-(6-Iodo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide
Starting compound: Preparation 53
Preparation 88
N-[(9-Iodo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropyl-aceta-
mide
Starting compound: Preparation 54
Preparation 89
N-(4-Iodo-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea
Starting compound: Preparation 55
Preparation 90
N-Cyclobutyl-6-iodo-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide
Starting compound: Preparation 56
Preparation 91
N-[2-(7-Iodo-3-naphthyl-1-naphthyl)ethyl]heptanamide
Starting compound: Preparation 57
Preparation 92
N-[2-(7-Iodo-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 58
Preparation 93
N-[2-(7-Iodo-1-naphthyl)ethyl]-3-butenamide
Starting compound: Preparation 59
Preparation 94
N-[2-(7-Iodo-1-naphthyl)ethyl]-2-bromoacetamide
Starting compound: Preparation 60
Preparation 95
N-[2-(7-Iodo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide
Starting compound: Preparation 61
Preparation 96
N-Cyclohexyl-4-(7-iodo-1-naphthyl)butanamide
Starting compound: Preparation 38
Preparation 97
N-[3-(7-Iodo-1-naphthyl)propyl]acetamide
Starting compound: Preparation 62
Preparation 98
N-[2-(2-Iodo-1-naphthyl)-1-methylethyl]propanamide
Starting compound: Preparation 63
Preparation 99
N-{2-[7-Iodo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide
Starting compound: Preparation 64
Preparation 100
N-Methyl-4-(5-iodobenzo[b]furan-3-yl)butanamide
Starting compound: Preparation 65
Preparation 101
N-[2-(5-Iodothieno[3,2-b]pyridin-3-yl)ethyl]acetamide
Starting compound: Preparation 66
Preparation 102
N-[2-(5-Iodo-1H-3-indolyl)ethyl]benzamide
Starting compound: Preparation 67
Preparation 103
N-[2-(2-Benzyl-5-iodobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide
Starting compound: Preparation 68
Preparation 104
N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]butanamide
Starting compound: Preparation 69
Preparation 105
N-[2-(6-Iodo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide
Starting compound: Preparation 70
Preparation 106
N-[2-(7-Iodo-3-phenyl-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 71
Preparation 107
N-[2-(7-Iodo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 72.1
Preparation 108
N-[2-(5-Iodobenzo[b]furan-3-yl)ethyl]acetamide
Starting compound: Preparation 72
Preparation 109
N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide
Step A: N-[2-(7-Vinyl-1-naphthyl)ethyl]-2-phenylacetamide
15 mmol of the product obtained in Preparation 73, 16 mmol of
vinyltributyltin and 0.43 mmol of
tetrakis(triphenylphosphine)palladium are heated in 30 ml of
N-methylpyrrolidinone at 110.degree. C. for 3 hours, with stirring.
After evaporating off the solvent, the residue is taken up in 20 ml
of dichloromethane and treated with 10% aqueous potassium fluoride
solution. After extraction, concentration under reduced pressure
and chromatography on silica gel, the pure title product is
obtained.
Step B: N-[2-(7-Formyl-1-naphthyl)ethyl]-2-phenylacetamide
To a solution of 10 mmol of the product obtained in Step A in a
mixture of 50 ml of dioxane and 25 ml of water there are added, at
ambient temperature, 1.10 g of osmium tetroxide in
2-methyl-2-propanol and then 8.70 g of sodium periodate. After
stirring overnight at ambient temperature, the suspension is
filtered and the filtrate is concentrated under reduced pressure.
The residue obtained is taken up in dichloromethane. The organic
phase is washed with water, dried and evaporated. The residue is
purified by chromatography on silica gel to yield the title
product.
Step C: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthoic acid
2.7 g of potassium permanganate in 50 ml of an acetone/water
mixture (50/50) are added, at ambient temperature, to a solution of
6.88 mmol of the product obtained in Step B in 30 ml of acetone.
The solution is stirred for 2 hours at ambient temperature and is
then filtered. The filtrate is concentrated under reduced pressure
and chromatographed on silica gel to yield the title product.
Step D: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthalenecarbonyl
chloride
5 mmol of the product obtained in Step C are dissolved in 40 ml of
thionyl chloride. After stirring under an inert atmosphere for 1
hour, the thionyl chloride is evaporated off under reduced pressure
to yield the title product.
Step E: N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide
A solution of the product obtained in Step D (20 mmol) in
dichloromethane (30 ml) containing tetrabutylammonium bromide (20
mg) is cooled in an ice bath. After adding sodium azide (24 mmol)
dissolved in 5 ml of water, the solution is stirred vigorously at
0.degree. C. for 2 hours. The organic phase is separated off,
washed with water (2.times.5 ml) and dried over magnesium sulphate.
After filtration, trifluoroacetic acid (30 mmol) is added and the
solution is stirred under reflux for 60 hours. After cooling, the
organic phase is washed with saturated sodium hydrogen carbonate
solution (2.times.5 ml) and is concentrated under reduced pressure.
The residue is then taken up in methanol (20 ml); water (80 ml) and
then potassium carbonate (30 mmol) are added. After stirring at
ambient temperature for 20 hours, the reaction mixture is
concentrated under reduced pressure to a volume of about 60 ml and
is then extracted 3 times with ether (3.times.50 ml). After drying
over sodium sulphate, the organic phase is filtered and then
evaporated under reduced pressure. The residue is chromatographed
on silica gel to yield the title product.
In Preparations 110 to 134 the procedure is as in Example 109,
starting from the appropriate substrate.
Preparation 110
N-[2-(7-Amino-1-naphthyl)ethyl]-2-bromoacetamide
Starting compound: Preparation 94
Preparation 111
N-[2-(7-Amino-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide
Starting compound: Preparation 95
Preparation 112
N-Cyclohexyl-4-(7-amino-1-naphthyl)butanamide
Starting compound: Preparation 96
Preparation 113
N-[3-(7-Amino-1-naphthyl)propyl]acetamide
Starting compound: Preparation 97
Preparation 114
N-[2-(2-Amino-1-naphthyl)-1-methylethyl]propanamide
Starting compound: Preparation 98
Preparation 115
N-[2-(7-Amino-3-benzoyl-1-naphthyl)ethyl]-N'-propylurea
Starting compound: Preparation 78
Preparation 116
N-[2-(7-Amino-1-naphthyl)ethyl]-3-butenamide
Starting compound: Preparation 93
Preparation 117
N-[2-(7-Amino-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 92
Preparation 118
N-{2-17-Amino-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide
Starting compound: Preparation 99
Preparation 119
N-Methyl-4-(5-aminobenzo[b]furan-3-yl)butanamide
Starting compound: Preparation 100
Preparation 120
N-[2-(5-Aminothieno[3,2-b]pyridin-3-yl)ethyl]acetamide
Starting compound: Preparation 101
Preparation 121
N-[2-(5-Amino-1H-3-indolyl)ethyl]benzamide
Starting compound: Preparation 102
Preparation 122
N-{2-[5-Amino-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]et-
hyl}acetamide
Starting compound: Preparation 81
Preparation 123
N-[2-(5-Amino-2-benzylbenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide
Starting compound: Preparation 103
Preparation 124
N-[(6-Amino-3,4-dihydro-2H-3-chromenyl)methyl]acetamide
Starting compound: Preparation 82
Preparation 125
N-[(6-Amino-2-phenyl-2H-3-chromenyl)methyl]butanamide
Starting compound: Preparation 104
Preparation 126
N-[2-(6-Amino-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide
Starting compound: Preparation 87
Preparation 127
N-[(9-Amino-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclo-propylacet-
amide
Starting compound: Preparation 88
Preparation 128
N-(4-Amino-2,3-dihydro-1H-2-phenalenyl)-N'-cyclopropylthiourea
Starting compound: Preparation 89
Preparation 129
N-[2-(7-Amino-3-phenyl-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 106
Preparation 130
N-Cyclobutyl-6-amino-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide
Starting compound: Preparation 90
Preparation 131
N-[2-(7-Amino-3-naphthyl-1-naphthyl)ethyl]heptanamide
Starting compound: Preparation 91
Preparation 132
N-[2-(5-Aminobenzo[b]furan-3-yl)ethyl]acetamide
Starting compound: Preparation 108
Preparation 133
N-[2-(7-Amino-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide
Starting compound: Preparation 107
Preparation 134
N-[2-(6-Amino-2,3-dihydro-1H-1-indenyl)ethyl]acetamide
Starting compound: Preparation 105
Preparations 135 to 145 are obtained by proceeding as in
Preparation 1, starting from the appropriate substrate.
Preparation 135
N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide
Preparation 136
N-[2-(7-Hydroxy-1-naphthyl)ethyl]benzamide
Preparation 137
N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclopropanecarboxamide
Preparation 138
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]benzamide
Preparation 139
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamide
Preparation 140
N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
Preparation 141
N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]cyclopropanecarboxamide
Preparation 142
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide
Preparation 143
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxami-
de
Preparation 144
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide
Preparation 145
N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide
Preparation 146
N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 142.
Preparation 147
N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 146.
Preparation 148
N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 147.
Preparation 149
N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 145.
Preparation 150
N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 149.
Preparation 151
N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 150.
Preparation 152
N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 144.
Preparation 153
N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 152.
Preparation 154
N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 153.
Preparation 155
N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 143.
Preparation 156
N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 155.
Preparation 157
N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 156.
Preparation 158
N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxami-
de
The procedure is as in Preparation 1.
Preparation 159
N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 158.
Preparation 160
N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 159.
Preparation 161
N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 160.
Preparation 162
N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 1.
Preparation 163
N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 162.
Preparation 164
N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 163.
Preparation 165
N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 164.
Preparation 166
N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 140.
Preparation 167
N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 166.
Preparation 168
N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 167.
Preparation 169
N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]benzamide
The procedure is as in Preparation 1.
Preparation 170
N-[2-(5-Bromo-1-benzothiophen-3-yl)ethyl]benzamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 169.
Preparation 171
N-[2-(5-Iodo-1-benzothiophen-3-yl)ethyl]benzamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 170.
Preparation 172
N-[2-(5-Amino-1-benzothiophen-3-yl)ethyl]benzamide
The procedure is as in Preparation 109, starting from the compound
obtained in Preparation 171.
Preparation 173
N-[2-(7-Bromo-1-naphthyl)ethyl]-2-furamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 135.
Preparation 174
N-[2-(7-Iodo-1-naphthyl)ethyl]-2-furamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 173.
Preparation 175
N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]benzamide
The procedure is as in Preparation 40, starting from the compound
obtained in Preparation 138.
Preparation 176
N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]benzamide
The procedure is as in Preparation 73, starting from the compound
obtained in Preparation 176.
EXAMPLE 1
N-{8-[2-([2-Phenylacetyl]amino)ethyl]-2-naphthyl}butanamide
A solution of butanoic acid chloride (11 mmol) dissolved in ether
(5 ml) is added dropwise to a solution of the product obtained in
Preparation 109 (10 mmol) in ether (10 ml) and triethylamine (2
ml). The solution is stirred at ambient temperature until the amine
has disappeared (monitored by TLC). At the end of the reaction, the
organic phase is washed with water, dried, concentrated under
reduced pressure and chromatographed on silica gel to yield the
title product.
EXAMPLE 2
N-{2-[7-{[(Cyclohexylamino)carbonyl]amino}-1-naphthyl]ethyl}-2-phenylaceta-
mide
A solution of cyclohexyl isocyanate in dichloromethane (5 ml) is
added to a solution of the product obtained in Preparation 109 (10
mmol) in dichloromethane (10 ml). Stirring is carried out at
ambient temperature until the starting amine has disappeared
(monitored by TLC); the reaction mixture is then evaporated and
concentrated under reduced pressure and is chromatographed on
silica gel to yield the title product.
EXAMPLE 3
N-{2-[7-([Anilinocarbothioyl]amino)-1-naphthyl]ethyl}-2-phenyl-acetamide
The procedure is as in Example 2, but the cyclohexyl isocyanate is
replaced by phenyl isothiocyanate to obtain the title product.
In Examples 4 to 16 the procedure is as in Example 1, starting from
appropriate reactants.
EXAMPLE 4
N-(8-{2-[(2-Bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexane-carboxamide
Starting compound: Preparation 110
EXAMPLE 5
N-{1-Hexyl-8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}benzamide
Starting compound: Preparation 111
EXAMPLE 6
N-{6-Benzoyl-8-[2-{[(propylamino)carbonyl]amino}ethyl]-2-naphthyl}-2,2-dim-
ethylpropanamide
Starting compound: Preparation 115
EXAMPLE 7
N-{3-[4-(Methylamino)-4-oxobutyl]benzo[b]furan-5-yl}-3-butynamide
Starting compound: Preparation 119
EXAMPLE 8
N-{3-[2-(Acetylamino)ethyl]-2-[4-fluorobenzyl]-1-methyl-1H-pyrrolo-[2,3-b]-
pyridin-5-yl}-3-phenyl-2-propenamide
Starting compound: Preparation 122
EXAMPLE 9
N-{3-[(Acetylamino)methyl]-3,4-dihydro-2H-6-chromenyl}-2-phenyl-propanamid-
e
Starting compound: Preparation 124
EXAMPLE 10
N-{5-[2-(Acetylamino)ethyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-hexanamide
Starting compound: Preparation 126
EXAMPLE 11
N-{2-[([2-Cyclopropylacetyl]amino)methyl]-2,3-dihydro-1H-benzo[f]-chromen--
9-yl}-4-(trifluoromethyl)benzamide
Starting compound: Preparation 127
EXAMPLE 12
N-{2-[([Cyclopropylamino]carbothioyl)amino]-2,3-dihydro-1H-4-phenalenyl}-4-
-ethoxybenzamide
Starting compound: Preparation 128
EXAMPLE 13
N-{8-[2-(Acetylamino)ethyl]-6-phenyl-2-naphthyl}-1-cyclopentane-carboxamid-
e
Starting compound: Preparation 129
EXAMPLE 14
N-Cyclobutyl-6-([2-cyclopropylacetyl)amino]-4,5-dihydro-3H-benzo[cd]-isobe-
nzofuran-4-carboxamide
Starting compound: Preparation 130
EXAMPLE 15
N-{8-[2-(Heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide
Starting compound: Preparation 131
EXAMPLE 16
N-{2-[6-(Acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide
Starting compound: Preparation 134
Examples 17 to 23 are obtained by proceeding as in Example 2,
starting from appropriate reactants.
EXAMPLE 17
N-Cyclohexyl-4-{7-[(anilinocarbonyl)amino]-1-naphthyl}butanamide
Starting compound: Preparation 112
EXAMPLE 18
N-{1-Methyl-2-[2-{[([morpholinomethyl]amino)carbonyl]amino}-1-naphthyl]eth-
yl}propanamide
Starting compound: Preparation 114
EXAMPLE 19
N-{2-[7-{[(Benzylamino)carbonyl]amino}-3-(cyclopropylmethyl)-1-naphthyl]et-
hyl}acetamide
Starting compound: Preparation 118
EXAMPLE 20
N-{2-[5-{[(Allylamino)carbonyl]amino}thieno[3,2-b]pyridin-3-yl]ethyl}-acet-
amide
Starting compound: Preparation 120
EXAMPLE 21
N-{2-[2-Benzyl-5-{[(1-ethynylamino)carbonyl]amino}benzo[b]furan-3-yl]ethyl-
}-1-cyclopropanecarboxamide
Starting compound: Preparation 123
EXAMPLE 22
N-{[6-{[([3-Methyl-2-butenyl]amino)carbonyl]amino}-2-phenyl-2H-3-chromenyl-
]methyl}butanamide
Starting compound: Preparation 125
EXAMPLE 23
N-[2-(7-{[(Cyclohexylamino)carbonyl]amino}-3-phenyl-1-naphthyl)-ethyl]acet-
amide
Starting compound: Preparation 129
In Examples 24 to 29 the procedure is as in Example 3, starting
from appropriate substrates.
EXAMPLE 24
N-{2-[7-{[(Isobutylamino)carbothioyl]amino}-1-naphthyl]ethyl}-2-bromoaceta-
mide
Starting compound: Preparation 110
EXAMPLE 25
N-{3-[7-{[([4-Methylbenzyl]amino)carbothioyl]amino}-1-naphthyl]-propyl}ace-
tamide
Starting compound: Preparation 113
EXAMPLE 26
N-Methyl-4-{5-[([1-ethynylamino]carbothioyl)amino]benzo[b]furan-3-yl}butan-
amide
Starting compound: Preparation 119
EXAMPLE 27
N-{2-[5-{[(Butylamino)carbothioyl]amino}-1H-3-indoly]ethyl}-benzamide
Starting compound: Preparation 121
EXAMPLE 28
N-{[9-([Anilinocarbothioyl]amino)-2,3-dihydro-1H-benzo[f]chromen-2-yl]meth-
yl}-2-cyclopropylacetamide
Starting compound: Preparation 127
EXAMPLE 29
N-Cyclobutyl-6-{[([2,3-dimethyl-2-butenyl]amino)carbothioyl]amino}-4,5-dih-
ydro-3H-benzo[cd]isobenzofuran-4-carboxamide
Starting compound: Preparation 130
EXAMPLE 30
N-Ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide
The procedure is as in Preparation 109, but instead of converting
the acid chloride into an amine, it is treated with an amine to
yield the title amide according to the procedure described
below.
A solution of the product obtained in Step D of Preparation 109
(3.5 mmol) in ether (10 ml) is added, dropwise, to a solution of
ethylamine (4 mmol) in ether (10 ml) and triethylamine (2 ml),
maintained between 0 and 5.degree. C. using an ice bath. Stirring
is carried out at ambient temperature until the acid chloride has
disappeared and the reaction mixture is then poured into a mixture
of ice (10 g) and concentrated HCl (0.1 ml). The organic phase is
washed with water, dried over magnesium sulphate, concentrated
under reduced pressure and chromatographed on silica gel to yield
the title product.
In Examples 31 to 50 the procedure is as in Example 30, but the
ethylamine and the product of Step D of Preparation 109 are
replaced by appropriate substrates.
EXAMPLE 31
N,N-Diethyl-8-{2-[2-1(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide
Starting compound: Preparation 74
EXAMPLE 32
N-Phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide
Starting compound: Preparation 75
EXAMPLE 33
N-(1-Ethynyl)-8-{2-[(cyclohexylcarbonyl)amino]ethyl}-2-naphthamide
Starting compound: Preparation 76
EXAMPLE 34
N-Benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide
Starting compound: Preparation 77
EXAMPLE 35
N-{2-[3-Benzoyl-7-(morpholinocarbonyl)-1-naphthyl]ethyl}-N'-propylurea
Starting compound: Preparation 78
EXAMPLE 36
N,N-Diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide
Starting compound: Preparation 79
EXAMPLE 37
N-Isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]-thioph-
ene-5-carboxamide
Starting compound: Preparation 80
EXAMPLE 38
N,N-Diethyl-3-[2-(acetylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H-pyrrol-
o[2,3-b]pyridine-5-carboxamide
Starting compound: Preparation 81
EXAMPLE 39
Ethyl
2-{[(4-{2-[(2-phenylacetyl)amino]ethyl}-3,4-dihydro-2H-6-chromenyl)c-
arbonyl]amino}acetate
Starting compound: Preparation 83
EXAMPLE 40
N-Cyclohexyl-N-(1-ethynyl)-4-[2-(acetylamino)ethyl]-6-thiochroman-carboxam-
ide
Starting compound: Preparation 85
EXAMPLE 41
N-Benzyl-3-(2-{[(propylamino)carbonyl]amino}ethyl-1,4-benzodioxin-6-carbox-
amide
Starting compound: Preparation 86
EXAMPLE 42
N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylacetyl)amino]methyl}-2,3,6,10b-te-
trahydro-1H-benzo[f]chromene-8-carboxamide
Starting compound: Preparation 88
EXAMPLE 43
N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihyd-
ro-1H-4-phenalenecarboxamide
Starting compound: Preparation 89
EXAMPLE 44
N-Cyclobutyl-N-trityl-4,5-dihydro-3H-benzo[cd]isobenzofuran-4,6-dicarboxam-
ide
Starting compound: Preparation 90
EXAMPLE 45
Ethyl
2-[({8-[2-heptanoylamino)ethyl]-6-naphthyl-2-naphthyl}carbonyl)-amin-
o]acetate
Starting compound: Preparation 91
EXAMPLE 46
N-(1-Ethynyl)-8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthamide
Starting compound: Preparation 94
EXAMPLE 47
N-Phenyl-1-hexyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide
Starting compound: Preparation 95
EXAMPLE 48
Ethyl
2-({[8-[2-(acetylamino)ethyl]-6-(cyclopropylmethyl)-2-naphthyl]-carb-
onyl}amino)acetate
Starting compound: Preparation 99
EXAMPLE 49
N-(1-Ethynyl)-2-benzyl-3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo-[b]fur-
an-5-carboxamide
Starting compound: Preparation 103
EXAMPLE 50
N-(1-Isopropyl-2-propynyl)-3-[(butynylamino)methyl]-2-phenyl-2H-6-chromene-
carboxamide
Starting compound: Preparation 104
EXAMPLE 51
N-Phenyl-8-(2-{methyl[(propylamino)carbothioyl]amino}ethyl)-2-naphthalenec-
arbothioamide
The product obtained in Example 32 is treated with Lawesson's
reagent to yield the title compound.
In Examples 52 to 57 the procedure is as in Example 51, taking the
appropriate starting substrate.
EXAMPLE 52
N-Benzyl-1-{2-[(2,2,2-trifluoroethanethioyl)amino]ethyl}-2-naphthalene-car-
bothioamide
Starting compound: Example 34
EXAMPLE 53
N,N-Diphenyl-3-[3-(ethanethioylamino)propyl]benzo[b]furan-5-carbothioamide
Starting compound: Example 36
EXAMPLE 54
N,N-Diethyl-3-[2-(ethanethioylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H--
pyrrolo[2,3-b]pyridine-5-carbothioamide
Starting compound: Example 38
EXAMPLE 55
N-Cyclohexyl-N-(1-ethynyl)-4-[2-(ethanethioylamino)ethyl]-6-thiochromancar-
bothioamide
Starting compound: Example 40
EXAMPLE 56
N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylethanethioyl)amino]methyl}-2,3,6,-
10b-tetrahydro-1H-benzo[f]chromene-8-carbothioamide
Starting compound: Example 42
EXAMPLE 57
N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihyd-
ro-1H-4-phenalenecarbothioamide
Starting compound. Example 43
In Examples 58 to 61 the procedure is as in Example 1, but the acid
chloride is replaced by the corresponding halogenocarboxylate.
EXAMPLE 58
Methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate
Starting compound: Preparation 132
Melting point=138 140.degree. C.
EXAMPLE 59
Ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate
Starting compound: Preparation 110
EXAMPLE 60
Methyl
N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate
Starting compound: Preparation 129
EXAMPLE 61
Hexyl
N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}-carbamate
Starting compound: Preparation 133
EXAMPLE 62
N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide
Step A: 3-Acetyl-4-hydroxybenzoic acid
166 mmol of aluminium chloride are added slowly to 150 ml of
nitrobenzene. 83 mmol of 4-acetylbenzoic acid are then added and
heating is carried out at 120.degree. C. for 2 hours. The mixture
is hydrolysed using 1.2 litres of ice-cold water and the aqueous
phase is acidified with 20 ml of concentrated HCl. Then, extraction
with ethyl acetate and washing with aqueous 5% sodium carbonate
solution are carried out. The aqueous phase is acidified with 6N
HCl and the precipitate obtained is dried and recrystallised.
Melting point=120 121.degree. C.
Step B: 3-(2-Bromoacetyl)-4-hydroxybenzoic acid
The compound obtained in Step A (32.2 mmol) is dissolved in glacial
acetic acid (40 ml) and then 48.3 mmol of bromine are added. The
mixture is heated at 80.degree. C. for 2 hours and is then
hydrolysed using ice-cold water. The precipitate obtained is
filtered off, washed with water until a pH of 5 6 is obtained, and
then dried and recrystallised.
Melting point=174 1 75.degree. C.
Step C: Methyl 3-bromoacetyl-4-hydroxybenzoate
The compound obtained in Step B (27.4 mmol) is dissolved in 150 ml
of MeOH, and 54.8 mmol of thionyl chloride are added dropwise in
the cold state. The mixture is then stirred for 1 hour at ambient
temperature and then for 2 hours at reflux. After evaporating off
the methanol and the thionyl chloride, the oily residue is taken up
in AcOEt, washed with water and then dried over MgSO.sub.4. The
solvent is evaporated off under reduced pressure and the solid
obtained is recrystallised.
Melting point=93 94.degree. C.
Step D: 5-(Methoxycarbonyl-3-benzo[b]furan-3-yl)acetonitrile
The compound obtained in Step C (15 mmol) is dissolved in 35 ml of
acetone. 30 mmol of potassium carbonate are added and the mixture
is stirred for 2 hours at ambient temperature. The precipitate
formed is filtered off, washed with acetone and the filtrate is
evaporated under reduced pressure. The benzofiranone formed is used
directly in the following step: 22.5 mmol of NaH are introduced
into a 250 ml round-bottomed two-necked flask which is placed in a
bath of ice/salt and under a nitrogen atmosphere. 22.5 mmol of
diethyl cyanophosphonate are added dropwise and the mixture is then
stirred for 20 minutes. The benzofuranone previously obtained, in
140 ml of anhydrous THF, is added and the mixture is stirred for 2
hours at ambient temperature. After hydrolysing on a pile of ice
and extracting with Et.sub.2O, the organic phase is dried over
MgSO.sub.4 and the solvent is then evaporated off under reduced
pressure. The title compound is purified by chromatography on a
silica gel column (eluant: CH.sub.2Cl.sub.2), and is then
recrystallised.
Melting point=125 126.degree. C.
Step E:
N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide
The 5-(methoxycarbonylbenzo[b]furan-3-yl)acetonitrile obtained in
Step D (6.46 mmol) is dissolved in acetic anhydride (30 ml) in an
autoclave, and 14.4 mmol of Raney nickel are added. After stirring
overnight at 60.degree. C. and under a hydrogen pressure of 60
bars, the catalyst is filtered off and washed with methanol. The
filtrate is evaporated to dryness and the chestnut-coloured
precipitate obtained is chromatographed on a silica gel column
using ethyl acetate as eluant and is then recrystallised.
Melting point=121 122.degree. C.
Elemental Microanalysis:
TABLE-US-00001 C H N % calculated: 64.36 5.78 5.36 % found: 64.14
5.81 5.28
EXAMPLE 63
Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate
Step A: Methyl 3-(2-aminoethyl)-1-benzofuran-5-carboxylate
hydrochloride
6.57 mmol of the compound obtained in Step D of Example 62 are
dissolved in 150 ml of methanol. The solution is introduced into an
autoclave and 28.8 mmol of Raney nickel are added. The solution is
saturated with ammonia, and then hydrogen is introduced until a
pressure of 60 bars is obtained. The solution is stirred for 4
hours at a temperature of 60.degree. C. After cooling, the catalyst
is filtered off, and the methanol is then evaporated off. The
residue is purified by chromatography on a silica gel column using
a mixture of dichloromethane/methanol (7/3) and then methanol as
eluant. The amine obtained is dissolved in absolute ethanol.
Stirring is carried out in an ice bath and gaseous hydrogen
chloride is bubbled through. The hydrochloride obtained is filtered
off under suction and dried in a desiccator.
Melting point=210 211.degree. C.
Step B: Methyl
3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate
1 mmol of the compound obtained in Step A is introduced into 30 ml
of anhydrous CH.sub.2Cl.sub.2. The temperature is lowered with the
aid of an ice bath, and 1.5 mmol of triethylamine and then 1.5 mmol
of 2-furoic acid chloride are added dropwise in succession. The
mixture is stirred for 20 minutes, and the organic phase is then
washed with water, dried over MgSO.sub.4 and evaporated. The
residue is purified by chromatography on a silica gel column and
the title product is recrystallised.
Melting point=116 118.degree. C.
Elemental Microanalysis:
TABLE-US-00002 C H N % calculated: 65.17 4.82 4.47 % found: 64.80
4.84 4.50
EXAMPLE 64
Methyl
3-{2-[(cyclopentylcarbonyl)amino]ethyl}1-benzofuran-5-carboxylate
The procedure is as in Example 63.
Melting point=122 123.degree. C.
EXAMPLE 65
Methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate
The procedure is as in Example 63.
Melting point=154 155.degree. C.
EXAMPLE 66
Methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate
Vinylacetic acid (1 mmol),
1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide
hydro-chloride (E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT)
(1.1 mmol) are dissolved in dichloromethane (30 ml) in a flask
cooled to -20.degree. C. After 30 minutes, the compound obtained in
Step A of Example 63 (1 mmol), dissolved in dichloromethane (20
ml), is added dropwise. The reaction mixture is stirred for 30
minutes at -20.degree. C. and then overnight at ambient
temperature. The dichloromethane is evaporated off and the residue
is purified by chromatography on a silica gel column.
Melting point=98 100.degree. C.
EXAMPLE 67
3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxamide
The ester (0.1 mol) obtained in Example 62, dissolved in an aqueous
20% ammonium hydroxide solution (50 ml), is heated for 5 hours at
60.degree. C. The reaction mixture is cooled and is then evaporated
to dryness. The residue obtained is purified by chromatography on a
silica gel column.
Melting point=206 208.degree. C.
Elemental Microanalysis:
TABLE-US-00003 C H N % calculated: 63.40 5.73 11.38 % found: 63.23
5.89 11.17
EXAMPLE 68
3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide
The same procedure is used as in Example 67.
Melting point=209 210.degree. C.
EXAMPLE 69
3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-carboxamide
The same procedure is used as in Example 67.
Melting point=110 112.degree. C.
Elemental Microanalysis:
TABLE-US-00004 C H N % calculated: 64.42 4.73 9.39 % found: 64.23
4.98 9.97
EXAMPLE 70
3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamid-
e
To the ester obtained in Example 62 (1 mmol), dissolved in methanol
(40 ml) in the hot state, there is added an aqueous 40% methylamine
solution (1.6 mmol), and the mixture is refluxed for 2 hours. The
reaction mixture is then cooled and the methanol is subsequently
evaporated off. The aqueous phase is extracted with ethyl acetate,
the organic phase is dried over magnesium sulphate and the solvent
is evaporated off. The residue is purified by chromatography on a
silica gel column.
Melting point=188 189.degree. C.
Elemental Microanalysis:
TABLE-US-00005 C H N % calculated: 67.11 6.34 9.78 % found: 67.00
6.34 9.77
EXAMPLE 71
3-[2-(Acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide
The same procedure is used as in Example 70.
Melting point=158 159.degree. C.
Elemental Microanalysis:
TABLE-US-00006 C H N % calculated: 64.59 6.20 10.76 % found: 64.27
6.13 10.44
EXAMPLE 72
3-{2-[(Cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamid-
e
The same procedure is used as in Example 70.
Melting point=170 171.degree. C.
EXAMPLE 73
3-[2-(Benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide
The same procedure is used as in Example 70.
EXAMPLE 74
N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide
Step A: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid
To the ester obtained in Example 62 (2 mmol), dissolved in methanol
(90 ml), there is added aqueous 30% sodium hydroxide solution (30
ml), and the mixture is stirred overnight. After evaporating off
the methanol, the temperature of the reaction mixture is lowered
with the aid of an ice bath and the mixture is acidified with
hydrochloric acid solution (6N). The aqueous phase is extracted
with ethyl acetate, and the organic phase is dried over magnesium
sulphate and then evaporated to dryness. The residue obtained is
recrystallised.
Melting point=210 211.degree. C.
Step B: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carbonyl azide
The acid (1 mmol) obtained in Step A is dissolved in acetone. The
temperature of the reaction mixture is lowered with the aid of an
ice bath, and triethylamine (1.5 mmol) and then ethyl chloroformate
(1.5 mmol) are added. After stirring for 15 minutes, sodium azide
(1.5 mmol), previously dissolved in water (1 ml of water per 400 mg
of sodium azide), is added and stirring is again carried out for 10
minutes. The mixture is extracted with ethyl acetate, and the
organic phase is then washed with water, dried over magnesium
sulphate and evaporated to dryness. The azide obtained is used,
without additional purification, in the following Step.
Step C:
N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroace-
tamide
To the azide obtained in Step B (460 mg, 1.68 mmol), dissolved in
dichloromethane, there is added trifluoroacetic acid (1.82 ml, 2.35
mmol) and stirring is carried out overnight. The reaction mixture
is washed with water and then with aqueous 10% sodium hydrogen
carbonate solution.
The organic phase is dried over magnesium sulphate and then
evaporated. The residue obtained is purified by chromatography on a
silica gel column using ethyl acetate as eluant.
Melting point=152 154.degree. C.
EXAMPLE 75
Methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate
The azide obtained in Step B of Example 74 (1 mmol) is heated at
80.degree. C. overnight and 5 ml of MeOH and 5 ml of toluene are
added. After evaporating off the solvent, the residue obtained is
purified by chromatography on a silica gel column.
Melting point=153 155.degree. C.
Elemental Microanalysis:
TABLE-US-00007 C H N % calculated: 63.56 6.00 9.27 % found: 63.27
6.02 9.14
EXAMPLE 76
tert-Butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate
The procedure is as in Examples 74 and 75.
Melting point=146 148.degree. C.
Elemental Microanalysis:
TABLE-US-00008 C H N % calculated: 64.12 6.97 8.79 % found: 64.03
6.58 8.67
EXAMPLE 77
tert-Butyl
3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate
To 1.98 mmol of the carbamate obtained in Example 76, dissolved in
dimethylformamide, there are added, in the cold state, 2.18 mmol of
sodium hydride, and stirring is carried out for 2 hours at ambient
temperature. 2.37 mmol of methyl iodide are added to the mixture
and stirring is carried out for 4 hours at ambient temperature. The
reaction mixture is hydrolysed, extracted with ethyl acetate, and
the organic phase is then washed with water and dried over
magnesium sulphate. The residue is recrystallised.
EXAMPLE 78
Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate
The procedure is as in Examples 74 and 75.
EXAMPLE 79
Methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate
The procedure is as in Examples 74 and 75.
EXAMPLE 80
N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide
Step A: N-{2-[7-(Benzylthio)-1-naphthyl]ethyl}acetamide
4.4 mmol of the compound obtained in Preparation 1 are dissolved in
20 ml of anhydrous CH.sub.2Cl.sub.2 and placed under a current of
nitrogen. 6.5 mmol of benzylthiol are added dropwise using a
syringe and then 8.8 mmol of triflic acid are added, before the
mixture is refluxed for 24 hours. After cooling, hydrolysis is
carried out using 10% Na.sub.2CO.sub.3 solution. The organic phase
is washed with 10% sodium hydroxide solution and then with water
until the washing waters are neutral, and is then dried and
evaporated. The residue is taken up in petroleum ether and
recrystallised from a toluene/cyclohexane mixture.
Melting point=80 83.degree. C.
Step B: 8-[2-(Acetylamino)ethyl]-2-naphthalenesulphonyl
chloride
3 mmol of the compound obtained in Step A are crushed in a mortar,
together with 13.1 mmol of iodosobenzene and 107 g of silica/HCl,
with the aid of a pestle. Dichloromethane is added and the silica
is filtered off and washed several times with CH.sub.2Cl.sub.2. The
filtrate obtained is evaporated and the residue is taken up in
petroleum ether and then filtered.
Step C: N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide
0.8 mmol of the compound obtained in Step B is dissolved in 10 ml
of CH.sub.2Cl.sub.2 and then 1.2 mmol of triethylamine are added.
The mixture is cooled with the aid of an ice bath and 1.2 mmol of
ammonium hydroxide solution are added dropwise. After stirring for
2 hours, the mixture is evaporated and the residue obtained is
recrystallised.
Melting point=194 196.degree. C.
EXAMPLE 81
N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide
The procedure is as in Example 80, but the ammonium hydroxide in
Step C is replaced by methylamine.
Melting point=155 156.degree. C.
By proceeding as in Example 80, but replacing, in Step A, the
compound of Preparation 1 by the appropriate substrate, and, in
Step C, the ammonium hydroxide by the appropriate amine, Examples
82 to 84 are obtained:
EXAMPLE 82
N-(2-{7-[(Methylamino)sulphonyl]-1-naphthy}ethyl)-2-furamide
Starting compound: Preparation 135
EXAMPLE 83
N-(2-{7-[(Ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide
Starting compound: Preparation 136
EXAMPLE 84
N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropane-carboxamide
Starting compound: Preparation 137
EXAMPLE 85
N-(3-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide
Starting compound: Preparation 16
EXAMPLE 86
N-(2-{5-[(Propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide
Starting compound: Preparation 18
EXAMPLE 87
N-(2-{5-[(Cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-benzamide
Starting compound: Preparation 138
EXAMPLE 88
N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide
Starting compound: Preparation 139
EXAMPLE 89
N-(2-{5-[(Hexylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carbo-
xamide
Starting compound: Preparation 140
EXAMPLE 90
N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carb-
oxamide
Starting compound: Preparation 140
EXAMPLE 91
N-(2-{2-Benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-acet-
amide
Starting compound: Preparation 19
EXAMPLE 92
N-(2-{5-[(Isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-cyclopropa-
necarboxamide
Starting compound: Preparation 141
EXAMPLE 93
N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-acet-
amide
Starting compound: Preparation 142
EXAMPLE 94
N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-cycl-
opropanecarboxamide
Starting compound: Preparation 143
EXAMPLE 95
N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-benz-
amide
Starting compound: Preparation 144
EXAMPLE 96
N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-fu-
ramide
Starting compound: Preparation 145
Examples 97 to 105 are obtained by proceeding as in Example 1, but
replacing the acid chloride by the corresponding
halogenocarboxylate.
EXAMPLE 97
Methyl
5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate
Starting compound: Preparation 126
EXAMPLE 98
Methyl
3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate
Starting compound: Preparation 124
EXAMPLE 99
Ethyl
3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate
Starting compound: Preparation 134
EXAMPLE 100
Methyl
3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate
Starting compound: Preparation 148
EXAMPLE 101
Methyl
3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate
Starting compound: Preparation 151
EXAMPLE 102
Methyl
3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate
Starting compound: Preparation 154
EXAMPLE 103
Methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]-pyridin-5-
-yl-carbamate
Starting compound: Preparation 157
EXAMPLE 104
Methyl
3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[3,2-b]-pyridin-5-
-yl-carbamate
Starting compound: Preparation 161
EXAMPLE 105
Ethyl
3-[2-(acetylamino)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl-carbamate
Starting compound: Preparation 165
Examples 106 to 108 are obtained by proceeding as in Example 1,
starting from the appropriate substrate.
EXAMPLE 106
N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}acetamide
Starting compound: Preparation 117
EXAMPLE 107
N-{2-[5-(Acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropane-carboxamide
Starting compound: Preparation 168
EXAMPLE 108
N-{2-[5-(Acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide
Starting compound: Preparation 172
Examples 109 to 112 are obtained by proceeding as in Preparation
109, condensing the appropriate amine with the intermediate acid
chloride.
EXAMPLE 109
3-[2-(Acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide
Starting compound: Preparation 147
EXAMPLE 110
N-(2-{7-[(Methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide
Starting compound: Preparation 174
EXAMPLE 111
3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-ethyl-1-benzofuran-5-carboxamide
Starting compound: Preparation 167
EXAMPLE 112
3-[2-(Benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide
Starting compound: Preparation 176
EXAMPLE 113
N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide
Step A: 7-Nitro-3,4-dihydro-1(2H)-naphthalenone
7 mmol of 1-oxo-1,2,3,4-tetrahydronaphthalene and 5 ml of
concentrated sulphuric acid are cooled in a freezer for 30 minutes.
The reaction mixture is then placed in a bath of alcohol at
-15.degree. C. on a cooling plate. A sulphonitric mixture (1.1 ml
of sulphuric acid and 0.73 ml of nitric acid) is prepared and
brought to the temperature of the reaction mixture before being
added dropwise, avoiding any drastic heating of the mixture.
Stirring is carried out for 15 minutes and then hydrolysis on a
pile of ice is carried out. The pale yellow precipitate obtained is
washed with water until the washing waters have a neutral pH and is
then dried in a desiccator and purified on a silica gel column.
Melting point=103.7 104.3.degree. C.
Step B:
2-[7-Nitro-3,4-dihydro-1(2H)-naphthalenylidene]acetonitrile
Using a 50 ml two-necked flask under a current of nitrogen and
placed in a bath of alcohol at -15.degree. C., 0.32 g of sodium
hydride is added in portions to 40 ml of THF, with magnetic
stirring, and then 1.4 g of diethyl cyanomethylphosphonate in 10 ml
of THF are added dropwise. After stirring for half an hour, when
the mixture is highly homogeneous, the flask is plunged into a
medium at -78.degree. C. (cryostat), and 1 g of the compound
obtained in Step A, dissolved in 20 ml of THF, is added dropwise.
Stirring under a current of nitrogen is carried out for 2 hours.
The reaction mixture is then brought to ambient temperature,
hydrolysed on ice and precipitated. After filtering under suction
and washing with water until the washing waters have a neutral pH,
extraction with 3 volumes of ether is carried out. The organic
phases are washed with 3 volumes of water and then dried. The grey
solid obtained is decolorised on carbon.
Melting point=98.1 98.5.degree. C.
Step C:
N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetami-
de
9 mmol of the compound obtained in Step B are dissolved in acetic
anhydride (100 ml) and then a small spatula of sodium acetate is
added. The mixture is introduced into an autoclave, Raney nickel is
added and autoclaving under a pressure of 40 bars is carried out
for 6 hours, with stirring at 50 60.degree. C. The mixture is
filtered and is rinsed with alcohol at 95.degree. C.; the solvent
is then evaporated off. Hydrolysis is carried out using 100 ml of
distilled water and extraction with 3 volumes of dichloromethane is
carried out. The organic phase is washed with 2 volumes of water,
dried over magnesium sulphate, filtered and evaporated. Rinsing
with an ether/dichloromethane mixture and trituration in ether are
carried out. The light-beige solid obtained is recrystallised.
Melting point=127.7 128.7.degree. C.
Elemental Microanalysis:
TABLE-US-00009 C H N % calculated: 70.04 8.08 10.21 % found: 69.74
8.14 10.43
EXAMPLE 114
Methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate
The procedure is as in Example 97.
Starting compound: Preparation 117
EXAMPLE 115
N-[2-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-a-
cetamide
A solution of the product obtained in Preparation 109 (10 mmol) in
ether (160 ml) is added very slowly, using a dropper to a solution
of malonyl dichloride (40 mmol) in ether (40 ml) and triethylamine
(2 ml). At the end of the reaction, the reaction mixture is
concentrated under reduced pressure. The residue is dried using a
vane pump and then taken up in ether. The organic phase is washed
with water, dried over magnesium sulphate, concentrated under
reduced pressure and then dried using a vane pump. The residue is
then taken up in 100 ml of 1,1,2,2-tetrachloroethane. The resulting
solution is then added dropwise to a solution of aluminium chloride
(30 mmol) in 50 ml of the same solvent under nitrogen. The mixture
is heated at 60.degree. C. until the reaction has ceased; the
reaction mixture is then poured into a mixture of ice (20 g) and
concentrated HCl (1 ml) and is stirred for one hour. The aqueous
phase is extracted twice with chloroform and then the combined
organic phases are dried over magnesium sulphate and concentrated
under reduced pressure. The residue is chromatographed on silica
gel to yield the title product.
In Examples 116 to 120 the procedure is as in Example 115, starting
from appropriate substrates.
EXAMPLE 116
N-Cyclohexyl-4-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butana-
mide
Starting compound: Preparation 112
EXAMPLE 117
N-[2-(7-Benzoyl-1,2-dioxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N'-prop-
ylurea
Starting compound: Preparation 115
EXAMPLE 118
N-Methyl-4-(7,9-dioxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanami-
de
Starting compound: Preparation 119
EXAMPLE 119
N-{2-[2-(4-Fluorobenzyl)-3-methyl-7,8-dioxo-3,6,7,8-tetrahydro-dipyrrolo[2-
,3-b:3,2-d]pyridin-1-yl]ethyl}acetamide
Starting compound: Preparation 122
EXAMPLE 120
N-[(8,10-Dioxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methy-
l]acetamide
Starting compound: Preparation 124
EXAMPLE 121
N-[2-(3-Oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-aceta-
mide
The product of Example 115 (3 mmol) is dissolved in acetic acid (70
ml). After several purges with argon, 10% palladium-on-carbon (600
mg) is added and the mixture is placed under a hydrogen atmosphere.
Stirring is carried out at ambient temperature until the end of the
reaction (monitored by TLC) and the palladium is filtered off over
Celite. The acetic acid is evaporated off to dryness and the
residue is chromatographed on silica gel to yield the title
product.
In Examples 122 to 126 the procedure is as in Example 121, starting
from appropriate substrates.
EXAMPLE 122
N-Cyclohexyl-4-(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butanamide
Starting compound: Example 116
EXAMPLE 123
N-[2-(7-Benzoyl-2-oxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N'-propylur-
ea
Starting compound: Example 117
EXAMPLE 124
N-Methyl-4-(9-oxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanamide
Starting compound: Example 118
EXAMPLE 125
N-{2-[2-(4-Fluorobenzyl)-3-methyl-8-oxo-3,6,7,8-tetrahydropyrrolo-[2,3-b:3-
,2-d]pyridin-1-yl]ethyl}acetamide
Starting compound: Example 119
EXAMPLE 126
N-[(8-Oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methyl]ace-
tamide
Starting compound: Example 120
EXAMPLE 127
N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexane-car-
boxamide
The product of Example 33 (10 mmol) and triethylene glycol are
introduced into a two-necked flask. Heating is carried out at 160
170.degree. C., under nitrogen and with stirring, for five hours.
The reaction mixture is poured into ice-cold water and is extracted
with ethyl acetate. The organic phase is washed with water and
dried over calcium chloride. After filtration, the organic phase is
concentrated under reduced pressure. The residue is chromatographed
on silica gel to yield the title product.
In Examples 128 to 132, the procedure is as in Example 127,
starting from appropriate substrates.
EXAMPLE 128
N-[2-(2-Benzyl-7-isopropyl-6-oxo-6,7-dihydrothieno[3,2-f]isoquinolin-1-yl)-
ethyl]acetamide
Starting compound: Example 37
EXAMPLE 129
N-[2-(3-Cyclohexyl-4-oxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoquino-
lin-10-yl)ethyl]acetamide
Starting compound: Example 40
EXAMPLE 130
N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-2-bromo-acetamide
Starting compound: Example 46
EXAMPLE 131
N-[2-(2-Benzyl-6-oxo-6,7-dihydrofuro[3,2-f]isoquinolin-1-yl)ethyl]-1-cyclo-
propanecarboxamide
Starting compound: Example 49
EXAMPLE 132
N-[(9-Isopropyl-7-oxo-3-phenyl-3,7,8,9-tetrahydrochromeno[6,5-c]-azepin-2--
yl)methyl]butanamide
Starting compound: Example 50
EXAMPLE 133
N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)e-
thyl]-2-phenylacetamide
Step A:
2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6--
yl-carbonyl]amino}acetic acid
A 0.5N aqueous solution of K.sub.2CO.sub.3 (10 ml) is added to the
product obtained in Example 39 (4 mmol) dissolved in methanol (10
ml). When the reaction has ceased, the solution is acidified to pH
6 7 using 1N hydrochloric acid solution. The reaction mixture is
extracted with dichloromethane. The organic phase is washed with
water, dried over magnesium sulphate and Is concentrated under
reduced pressure. The residue is chromatographed on silica gel to
yield the title product.
Step B:
2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6--
yl-carbonyl]amino}acetyl chloride
The product obtained in Step A (3 mmol), dissolved in thionyl
chloride, is stirred at 60.degree. C. under a current of nitrogen
for one hour. The thionyl chloride is evaporated off under reduced
pressure and the residue is dried with the aid of a vane pump to
yield the title product.
Step C:
N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinoli-
n-10-yl)-ethyl]-2-phenylacetamide
The product obtained in Step B (3 mmol), dissolved in
1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution
of aluminium chloride (10 mmol) in the same solvent (20 ml) under
nitrogen. The reaction mixture is heated at 60.degree. C., with
stirring, until the reaction has ceased. The solution is then
poured into a mixture of ice (10 g)/concentrated HCl (0.3 ml) and
stirring is carried out for one hour. The aqueous phase is
extracted twice with chloroform; the combined organic phases are
then dried over magnesium sulphate and concentrated under reduced
pressure. The residue is chromatographed on silica gel to yield the
title product.
In Examples 134 to 135 the procedure is as in Example 133, starting
from appropriate reactants.
EXAMPLE 134
N-[2-(1,4-Dioxo-8-naphthyl-1,2,3,4-tetrahydro[f]isoquinolin-10-yl)-ethyl]h-
eptanamide
Starting compound: Example 45
EXAMPLE 135
N-{2-[8-(Cyclopropylmethyl)-1,4-dioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinol-
in-10-yl]ethyl}acetamide
Starting compound: Example 48
In Examples 136 to 138 the procedure is as in Example 122, starting
from appropriate substrates.
EXAMPLE 136
N-[2-(4-Oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)-ethy-
l]-2-phenylacetamide
Starting compound: Example 133
EXAMPLE 137
N-[2-(4-Oxo-8-naphthyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-10-yl)-ethyl]-
heptanamide
Starting compound: Example 134
EXAMPLE 138
N-{2-[8-(Cyclopropylmethyl)-4-oxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-1-
0-yl]ethyl}acetamide
Starting compound: Example 135
EXAMPLE 139
N-[2-(4-Thioxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexaneca-
rbothioamide
The product obtained in Example 127 is treated with Lawesson's
reagent to yield the title compound. Examples 140 to 142 are
obtained by proceeding as in Example 139.
EXAMPLE 140
N-[2-(3-Cyclohexyl-4-thioxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoqu-
inolin-10-yl)ethyl]acetamide
Starting compound: Example 129
EXAMPLE 141
N-[2-(1,4-Dithioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-y-
l)ethyl]-2-phenylethanethioamide
Starting compound: Example 133
EXAMPLE 142
N-{2-[8-(Cyclopropylmethyl)-4-thioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinoli-
n-10-yl]ethyl}ethanethioamide
Starting compound: Example 138
EXAMPLE 143
N-Cyclohexyl-4-(1-hydroxy-3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)b-
utanamide
A solution of the product obtained in Example 116 (2 mmol)
dissolved in methanol (10 ml) is added dropwise to a suspension of
sodium hydride (2.2 mmol) in methanol (50 ml) at -40.degree. C.
Stirring is carried out until the starting compound has completely
disappeared (about 3 hours). At the end of the reaction, the
solution is poured into water (30 ml). The reaction mixture is
concentrated under reduced pressure to a volume of about 30 ml and
is then extracted with ethyl acetate. The aqueous phase is washed
with water, dried over magnesium sulphate and concentrated under
reduced pressure. The residue is chromatographed on silica gel to
yield the title product.
In Examples 144 and 145, the procedure is as in Example 143.
EXAMPLE 144
N-[(10-Hydroxy-8-oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-
methyl]acetamide
Starting compound: Example 120
EXAMPLE 145
N-[2-(1-Hydroxy-4-methyl-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-
-phenylacetamide
Starting compound: Example 133
EXAMPLE 146
Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate
The procedure is as in Examples 74 and 75.
EXAMPLE 147
Methyl
3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate
The procedure is as in Examples 74 and 75.
EXAMPLE 148
Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate
The procedure is as in Example 63.
EXAMPLE 149
Methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate
The procedure is as in Example 63.
EXAMPLE 150
3-[2-(Benzoylamino)ethyl]-1-benzofuran-5-carboxamide
The procedure is as in Example 67.
EXAMPLE 151
Methyl 8-[2-(3-butenoylamino)ethyl]-2-naphthyl-carbamate
The procedure is as in Examples 74 and 75.
EXAMPLE 152
N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}-4-fluorobenzamide
The procedure is as in Example 1, starting from the compound
obtained in Preparation 117.
EXAMPLE 153
Ethyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate
The procedure is as in Example 62.
Pharmacological Study
EXAMPLE A
Acute Toxicity Study
Acute toxicity was evaluated after oral administration to groups
each comprising 8 mice (26.+-.2 grams). The animals were observed
at regular intervals during the course of the first day, and daily
for the two weeks following treatment. The LD.sub.50 (dose that
causes the death of 50% of the animals) was evaluated and
demonstrated the low toxicity of the compounds of the
invention.
EXAMPLE B:
Melatonin Receptor Binding Study on Pars Tuberalis Cells of
Sheep
Melatonin receptor binding studies of the compounds of the
invention were carried out according to conventional techniques on
pars tuberalis cells of sheep. The pars tuberalis of the
adenohypophysis is in fact characterised in mammals by a high
density of melatonin receptors (Journal of Neuroendocrinology, 1,
pp. 1 4, 1989).
Protocol
1) Sheep pars tuberalis membranes are prepared and used as target
tissue in saturation experiments to determine the binding
capacities and affinities for 2-[.sup.125I]-iodomelatonin. 2) Sheep
pars tuberalis membranes are used as target tissue in competitive
binding experiments using the various test compounds in comparison
with melatonin.
Each experiment is carried out in triplicate and a range of
different concentrations is tested for each compound. The results
enable the determination, after statistical processing, of the
binding affinities of the compound tested.
Results
The compounds of the invention appear to have a strong affinity for
melatonin receptors.
EXAMPLE C
1. Melatonin mt.sub.1 and MT.sub.2 Receptor Binding Study
The mt.sub.1 or MT.sub.2 receptor binding experiments are carried
out using 2-[.sup.125I]-melatonin as reference radioligand. The
radioactivity retained is determined using a liquid scintillation
counter.
Competitive binding experiments are then carried out in triplicate
using the various test compounds. A range of different
concentrations is tested for each compound. The results enable the
binding affinities of the compounds tested (IC.sub.50) to be
determined.
2. Study of Binding to MT.sub.3 Melatonin Binding Sites
The MT.sub.3 site binding experiments are carried out on hamster
brain membranes using 2-[.sup.125I]-melatonin as reference
radioligand. The membranes are incubated for 30 minutes with the
2-[.sup.125I]-melatonin at a temperature of 4.degree. C. and at
different concentrations of the test compounds. After incubation,
the membranes are quickly filtered and then washed with cold buffer
using a filtration system. The radioactivity fixed is measured
using a scintillation counter. The IC.sub.50 values (concentration
inhibiting specific binding by 50%) are calculated from competition
curves according to a non-linear regression model.
The IC.sub.50 values found for the compounds of the invention
demonstrate binding to one or other of the receptor sub-types, the
values being .ltoreq.10 .mu.M.
EXAMPLE D
Action of the Compounds of the Invention on the Circadian Rhythms
of Locomotive Activity of the Rat
The involvement of melatonin in influencing, by day/night
alternation, the majority of physiological, biochemical and
behavioural circadian rhythms has made it possible to establish a
pharmacological model for research into melatoninergic ligands.
The effects of the molecules are tested on numerous parameters and,
in particular, on the circadian rhythms of locomotive activity,
which are a reliable indicator of the endogenous circadian
clock.
In this study, the effects of such molecules on a particular
experimental model, namely the rat placed in temporal isolation
(permanent darkness), is evaluated.
Experimental Protocol
One-month-old male rats are subjected, as soon as they arrive at
the laboratory, to a light cycle of 12 hours' light per 24 hours
(LD 12:12).
After 2 to 3 weeks' adaptation, they are placed in cages fitted
with a wheel connected to a recording system, in order to detect
the phases of locomotive activity and thus monitor the nychthemeral
rhythms (LD) or circadian rhythms (DD).
As soon as the rhythms recorded show a stable pattern during the
light cycle LD 12:12, the rats are placed in permanent darkness
(DD).
Two to three weeks later, when the free course (rhythm reflecting
that of the endogenous clock) is clearly established, the rats are
given a daily administration of the molecule to be tested.
The observations are made by means of visualisation of the rhythms
of activity: influence on the rhythms of activity by the light/dark
cycle, disappearance of the influence on the rhythms in permanent
darkness, influence on the activity by the daily administration of
the molecule; transitory or durable effect.
A software package makes it possible: to measure the duration and
intensity of the activity, the period of the rhythm of the animals
during free course and during treatment, possibly to demonstrate by
spectral analysis the existence of circadian and non-circadian (for
example ultradian) components. Results
The compounds of the invention clearly appear to allow powerful
action on the circadian rhythm via the melatoninergic system.
EXAMPLE E
Light/Dark Cages Test
The compounds of the invention are tested on a behavioural model,
the light/dark cages test, which allows the anxiolytic activity of
the compounds to be demonstrated.
The apparatus consists of two polyvinyl boxes covered with
Plexiglass. One of the boxes is in darkness. A lamp is placed above
the other box, yielding a light intensity of approximately 4000 lux
in the centre of the box. An opaque plastic tunnel separates the
light box from the dark box. The animals are tested individually
for a session of 5 minutes. The floor of each box is cleaned
between each session. At the start of each test, the mouse is
placed in the tunnel, facing the dark box. The time spent by the
mouse in the illuminated box and the number of passages through the
tunnel are recorded after the first entry into the dark box.
After administration of the compounds 30 minutes before the start
of the test, the compounds of the invention significantly increase
the time spent in the illuminated cage and the number of passages
through the tunnel, which demonstrates the anxiolytic activity of
the compounds of the invention.
EXAMPLE F
Activity of Compounds of the Invention on the Caudal Artery of the
Rat
The compounds of the invention were tested in vitro on the caudal
artery of the rat. Melatoninergic receptors are present in those
vessels, thus providing a relevant pharmacological model for
studying melatoninergic ligand activity. The stimulation of the
receptors can cause either vasoconstriction or dilation depending
on the arterial segment studied.
Protocol
One-month old rats are accustomed to a light/dark cycle of 12 h/12
h during a period of 2 to 3 weeks.
After sacrifice, the caudal artery is isolated and maintained in a
highly oxygenated medium. The arteries are then cannulated at both
ends, suspended vertically in an organ chamber in a suitable medium
and perfused via their proximal end. The pressure changes in the
perfusion flow enable evaluation of the vasoconstrictive or
vasodilatory effect of the compounds.
The activity of the compounds is evaluated on segments that have
been pre-contracted by phenylephrine (1 .mu.M). A
concentration/response curve is determined non-cumulatively by the
addition of a concentration of the test compound to the
pre-contracted segment. When the observed effect reaches
equilibrium, the medium is changed and the preparation is left for
20 minutes before the addition of the same concentration of
phenylephrine and a further concentration of the test compound.
Results
The compounds of the invention significantly modify the diameter of
caudal arteries pre-constricted by phenylephrine.
EXAMPLE G
Pharmaceutical Composition: Tablets
TABLE-US-00010 1000 tablets each comprising 5 mg of methyl 5 g
3-{2-[(cyclopropylcarbonyl)-
amino]ethyl}-1-benzofuran-5-yl-carbamate (Example 75) wheat starch
20 g maize starch 20 g lactose 30 g magnesium stearate 2 g silica 1
g hydroxypropyl cellulose 2 g
* * * * *